AU2005254808A1 - Alkynyl derivatives as modulators of metabotropic glutamate receptors - Google Patents

Alkynyl derivatives as modulators of metabotropic glutamate receptors Download PDF

Info

Publication number
AU2005254808A1
AU2005254808A1 AU2005254808A AU2005254808A AU2005254808A1 AU 2005254808 A1 AU2005254808 A1 AU 2005254808A1 AU 2005254808 A AU2005254808 A AU 2005254808A AU 2005254808 A AU2005254808 A AU 2005254808A AU 2005254808 A1 AU2005254808 A1 AU 2005254808A1
Authority
AU
Australia
Prior art keywords
alkyl
heteroaryl
cycloalkyl
alkylhalo
ynyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
AU2005254808A
Other versions
AU2005254808B2 (en
Inventor
Anne-Sophie Bessis
Christelle Bolea
Beatrice Bonnet
Mark Epping-Jordan
Nicholas Poirier
Sonia-Maria Poli
Jean-Philippe Rocher
Yves Thollon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Addex Pharmaceuticals SA
Original Assignee
Addex Pharmaceuticals SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Addex Pharmaceuticals SA filed Critical Addex Pharmaceuticals SA
Publication of AU2005254808A1 publication Critical patent/AU2005254808A1/en
Assigned to ADDEX PHARMA SA reassignment ADDEX PHARMA SA Request for Assignment Assignors: ADDEX PHARMACEUTICALS SA
Application granted granted Critical
Publication of AU2005254808B2 publication Critical patent/AU2005254808B2/en
Priority to AU2012205182A priority Critical patent/AU2012205182A1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Description

WO 2005/123703 PCT/IB2005/002390 I NOVEL ALKYNYL DERIVATIVES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS SUMMARY OF THE INVENTION
(CH
2 )n-X I The present invention provides new compounds of formula I, wherein W, n, X and W' are defined as in formula I; invention compounds are modulators of metabotropic glutamate receptors - subtype 5 ("mGluR5") which are useful for the treatment of central nervous system disorders as well as other disorders modulated by mGluR5 receptors. BACKGROUND OF THE INVENTION Glutamate, the major amino-acid transmitter in the mammalian central nervous system (CNS), mediates excitatory synaptic neurotransmission through the activation of ionotropic glutamate receptors receptor-channels (iGluRs, namely NMDA, AMPA and kainate) and metabotropic glutamate receptors (mGluRs). iGluRs are responsible for fast excitatory transmission (Nakanishi S. et al., (1998) Brain Res. Rev., 26:230 235) while mGluRs have a more modulatory role that contributes to the fine-tuning of synaptic efficacy. Glutamate is associated with numerous physiological functions such as long-term potentiation (LTP), a process believed to underlie learning and memory but also cardiovascular regulation, sensory perception, and the development of synaptic plasticity. In addition, glutamate plays an important role in the patho physiology of different neurological and psychiatric diseases, especially when an imbalance in glutamatergic neurotransmission occurs. The mGluRs are seven-transmembrane G protein-coupled receptors. The eight members of the family are classified into three groups (Groups 1, II & III) according to their sequence homology and pharmacological properties (Schoepp D.D. et al. (1999) Neuropharmacology, 38:1431-1476). Activation of mGluRs leads to a large variety of intracellular responses and activation of different transductional cascades. Among mGluR members, the mGluR5 subtype is of high interest for counterbalancing the deficit or excesses of neurotransmission in neuropsychatric diseases. mGluR5 belongs to Group I and its activation initiates cellular responses through G-protein mediated mechanisms. mGluR5 is coupled to phospholipase C and stimulates phosphoinositide hydrolysis and intracellular calcium mobilization. mGluR5 proteins have been demonstrated to be localized in post-synaptic elements adjacent to the post-synaptic density (Lujan R. et al. (1996) Eur. J. Neurosci. 8:1488 500; Lujan R. et al. (1997) J. Chem. Neuroanat., 13:219-41) and are also detected in the pre-synaptic elements (Romano C. et al. (1995) J. Comp. Neurol. 355:455-69). MGluR5 receptors can therefore modify the post-synaptic responses to neurotransmitter or regulate neurotransmitter release.
WO 2005/123703 PCT/IB2005/002390 2 In the CNS, mGIuR5 receptors are abundant mainly throughout cortex, hippocampus, caudate-putamen and nucleus accumbens. As these brain areas have been shown to be involved in emotion, motivational processes and in numerous aspects of cognitive function, mGluR5 modulators are predicted to be of therapeutic interest. A variety of clinical indications have been suggested to be targets for the development of subtype selective mGluR modulators. These include epilepsy, neuropathic and inflammatory pain, numerous psychiatric disorders (eg anxiety and schizophrenia), movement disorders (eg Parkinson disease), neuroprotection (stroke and head injury), migraine and addiction/drug dependency (for reviews, see Brauner-Osborne H. et al. (2000) J. Med. Chem. 43:2609-45; Bordi F. and Ugolini A. (1999) Prog. Neurobiol. 59:55-79; Spooren W. et al. (2003) Behav. Pharmacol. 14:257-77). mGluR5 receptor is considered as a potential drug target for the treatment of psychiatric and neurological disorders Anxiety Disorders, Attentional disorders, Eating Disorders, Mood Disorders, Psychotic Disorders, Cognitive Disorders, Personality Disorders and Substance of Abuse related disorders Other research supports a role of mGluR5 modulation in the treatment of Fragile X syndrome (Laura N. Antar et al. The Journal of Neuroscience, March 17, 2004, 24-11, 2648-2655, Weiler I.J., Proc.Natl.Acad.Sci. USA, 1997, 94, 5395-5400), Obesity and Gastro-Esophageal Reflux Disease (Blackshaw L.A. et al., presentation at the conference Neurogastroentorology & Mortility, Madison, Wisconsin, 14 November 2001). International Patent Publications W003/104206, GB2124227, W003/050087 and W003/013247 describe 3-phenoxyprop-1-ynyl and 3-pyridinoxyprop-1-ynyl, having herbicidal properties. In US6166060, 4-(5-phenylpent-1-ynyl)-lH-imidazole is described as an H3 histamine antagonist. International patent publications W099/02497, WO01/16121 and W002/46166 describe heteroaryl ethynyl compounds and their use as metabotropic glutamate receptor antagonists. International patent publications W02005/044265, W02005/044266 and W02005/044267 disclose a class of 3-(pyridin-2-yl)prop-2 ynyl derivatives as being useful in GERD indication. Compounds of general formula I can show potent activity and selectivity on mGluR5 receptor. The compounds of the invention can demonstrate advantageous properties over compounds of the prior art. Improvements have been observed in one or more of the following characteristics of the compounds of the invention: the potency on the target, the selectivity for the target, the solubility, the bioavailability, the brain penetration, and the activity in behavioural models of psychiatric and neurological disorders. The present invention' relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 modulators.
WO 2005/123703 PCT/IB2005/002390 3 FIGURES Figure 1 shows that the representative Example 256 of the invention significantly attenuates marble burying in mice at doses of 30mg/kg po. Figure 2 shows that the representative Example 255 of the invention significantly attenuates marble burying in mice at doses of 50mg/kg po. Figure 3 shows that the representative Example 256 of the invention significantly increases punished drinking in rats at doses of 1 0mg/kg po. Figure 4 shows that the representative Example 130 of the invention significantly increases punished drinking in rats at doses of 30mg/kg po. DETAILED DESCRIPTION OF THE INVENTION According to the present invention, there are provided new compounds of the general formula I W - (CH 2 )n-X I Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein: W is a 5-, 6-heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: WO 2005/123703 PCT/IB2005/002390 4 R2 R 2 R 2 O R R 3 -N RR x R R 3 3 -R-N R R R R R N R N N N AR N
R
2 R1 RR R 1 R R
----
N I N R R2 A R3<N NA R ~
R
2 RR R A'
R
3 R' R 3 R- R0 R2 "NR 2 N R
-'-N-
R' , R 2
,R
3 , R 4 , R and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Cr-C 6 -alkyl, Cr-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-CNC 6 -alkyl, O-CrCs-alkylhalo, 0-C 3
-C
6 -alkynyl, 0-C 3
-C
6 alkenyl, 0-C 2
-C
6 -alkyl-OR , O-C 3
-C
7 -cycloalkyl, 0-CrC 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, O-C 3
-C
7 -cycloalkylC 1
-C
6 -alkyl, 0 heteroaryl, heteroaryl, C-C6-alkyl-heteroaryl, aryl, 0-aryl, CI-C 6 alkylaryl, C-C 6 -alkylhalo-OR 6 , C 3
-C
6 -alkynyl-OR 6 , C 3
-C
6 -alkenyl OR , CO-C 6 -alkyl-S-R', O-C 2
-C
6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R 6, O
C
2
-C
6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=O) 2
-R
6 , O-CI-C 6 -alkyl-S(=0) 2 R 6 , Co-C 6 -alkyl-NR 6
R
7 , 0-C 2
-C
6 -alkyl-NR 6
R
7 , Co-C 6 -alkyl
S(=O)
2
NR
6
R
7 , Co-C 6 -alkyl-NR -S(=O) 2
R
7 , O-C-C 6 -alkyl S(=0) 2 NR 6R7, O-Cr-C 6 -alkyl-NR -S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O) NR R7, Co-C 6 -alkyl-NR 6
C(=O)-R
7 , 0-C-C6-alkyl-C(=0)-NR6R, O
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl C(=0)-OR 6 , O-C 2 -C6-alk(=O)-(=O)-R 6 , O-C-C 6 -alkyl-C(=O)-OR , Co-C 6 -alkyl-C(=O)-R 6 , O-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR 6
R
7 or Co-C 6 -alkyl-NR 6
-C(=O)
NR
7 R! substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C-C 6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C-C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-Cr-C 6 alkylaryl, Ci-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl; R, R7 and R are each independently selected from the group consisting of hydrogen, an optionally substituted Cr-C 6 -alkyl, C 1
-C
6
-
WO 2005/123703 PCT/IB2005/002390 5 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkCnyl, C 3 -Crcycloalkyl, C 3
-C
cycloalkyl-C 1
-C
6 -alkyl, heteroaryl, C 1
-C
6 -alkyl-heteroaryl, aryl; ZI, Z2, Z , Z4, Z , Z6, Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; mis an integer from I to 5; n is an integer from 1 to 6; X is selected from an optionally substituted CI-C 6 -alkyl, Ci-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-C 1
-C
6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, C 1
-C
6 -alkyl-0,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C 1
-C
6 alkylhalo-0, C 3
-C
6 -alkynyl-0, C 3
-C
6 -alkenyl-0, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6 -NRS(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR, Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=0), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=0)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=0)-O, Co-C 6 -alkyl-O-C(=O)-NR', Co-C 6 alkyl-NR 9
-C(=O)-NR
0 , Co-C 6 -alkyl-NR 9
-C(=NR'
0 )NR , Co-C 6 -alkyl
(C=NR
9 )NRio, CO-C6-all-C(=0)-O-CO-C6-all, Co-C 6 -alkyl-C(=0)
NR
9
-CO-C
6 -alky1, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R', R" 0 and R"' are each independently selected from hydrogen, an optionally substituted Ci-C 6 -alkyl, C 1
-C
6 -alkylhalo, C 2
-C
6 -alkynyl, C 2 C 6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalky-C1-C 6 -alkyl, heteroaryl,
C
1
-C
6 -alkyl-heteroaryl, aryl, heterocycle; W' denotes a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0 and S, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0 and S, provided that W' is a aryl, heteroaryl or heterocycle selected from the group of formula: WO 2005/123703 PCT/1B20051002390 6 0 Gq Iq BT B1 Gq'r- N ~ G~ N G' Gq Gq N >Gq Gqo N ~ -~ 0 1 ' ' -T '-\15 NN N N N N G N G ,,zl.:zi I- N- 3qI~z I >G G Gq -'/Gq- I />+~ ~ N~~/ ' ~0 1: B 2 N C( 00 0 G "N-q-I -q G" NN/ N cI 1 N 0 0 Gq IW G >== Gq I I G- 1 0 0N 0 GI groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1
-C
6 alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynylI, C 2
-C
6 -alkenyl, O-Cl-0 6 -alkyl,
O-CI-C
6 -alkylhalo, O-C 3
-C
6 -alkynYl, O-C 3
-C
6 -alkcnyl, O-C 2
-C
6 -alkyl OR 1 2
O-C
3
-C
7 -cycloalkyl, O-Cl-C 6 -alkyl-heteroaryl, O-C 1
-C
6 alkylaryl, CO-C 6 -alkyl-OR 1 2 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloallcyl-C 1 C 6 -alkyl, O-C 3
-C
7 -cycloalkyl-C,-C 6 -alkcyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-hete~roaryl, aryl, 0-aryl, Ci-C 6 -alk~4 l CC-alkylhalo
OR'
2 , C 3
-C
6 -alkynyl-OR' 2 , C 3
-C
6 -aflenyl-OR' , CO-C 6 -alkyl-S-R',0
C
2
-C
6 -alkyl-S-R' 2 , CO-C 6 -alkyl-S(=O)-R' 2 , O-C 2
-C
6 -alkyl-S(=O)-R 2
CO-C
6 -alkyl-S(=0) 2 -R 1 2 , O-C 1
-C
6 -alkyl-S(=O) 2 -R'1 2 , CO-C 6 -alkyl
NR
2
R
1 , OC 2 -C,-alkyl-NR' 2
R'
3 , Co-C 6 -alkYl-S(=O),Nk'RR, C,-.C, alkyl-NR' 2
-S(=O)
2
R'
3 , O-Ci-C 6 -alkyl-S(=O) 2 NR1 2 R1 3 , O-C 2
-C
6 -alkyl NR121 13 Y NR _S(=0O) 2
R'
3
CO-C
6 -alkyl-C(=O)-NR2 R 3, CO-C 6 -alkcyl NR"C(=O)-R 1, O-Ci-C 6 -al~kylC(=O)-NR2 R 3, O-C 2
-C
6 -alkyl NR1 2 C(=O)-R 1 3 , C 0
-C
6 -alkyl-OC(=O)-R 1 2 , CO-C 6 -alkyl-C(=O)-OR 1 2 ,
O-C
2
-C
6 -allcyl-OC(=O)-R' 2 , O-Cl-C 6 -alkyl-C(=O)-OR 1 2 , CO-C 6 -- alkyi C(=O)-R 1 2 , O-Cl-C 6 -alkyl-C(=O)-R'1 2 , CO-C 6 -alkyl-NR 12
-C(=O-)-OR'
3 ,
CO-C
6 -alkyl-O-C(=O)-NR 12R Or C0-C 6 -a lkylNR' 2 -C(=O)-NR1 3 R 1 4 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloall, heterocycloalkcyl or WO 2005/123703 PCT/IB2005/002390 7 heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-C-C-alkyl-heteroaryl, 0-C-C 6 alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, O-C 3
-C
7 cycloalkyl-Cl-C 6 -alkyl, 0-heteroaryl, heteroaryl, CI-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5; R , R3 and R 14 are each independently selected from the group consisting of hydrogen, an optionally substituted CrC 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2 -C-alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl;
Z
9 , Z 10 , Z", Z1 2 , Z1 3 , Z1 4 , Z 15 , Z 16 and Z 1 7 are each independently selected from the group consisting of -C=, -C=C-, -C(=O)-, -C(=S)-, C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to SGq groups;
B
1 , B 2 and B 3 are each selected independently from C, C=C, C=N, S, o or N which may further be substituted by one Gq group; Any N may be an N-oxide; provided that: when X is independently selected from NR 15 , 0, S or an optionally substituted CI-C 6 -alkyl, n is 1, W is an optionally substituted 2 pyridinyl and R 15 is independently selected from hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2 C 6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CI-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl or aryl, W' can not be an optionally substituted aryl; when X is 0, n is 1 and W' is an optionally substituted aryl or heteroaryl, W can not be an optionally substituted 3-pyridazinyl or 4 pyrimidinyl; when X is CH 2 , n is 1 and W' is aryl, W can not be 2-phenyloxazol-4 yl, 4-phenyloxazol-2-yl, 4-(3-(benzyloxy)propyl)-oxazol-2-yl, 4 phenylthiazol-2-yl, 4-methylthiazol-2-yl or benzo[djoxazol-2-yl, benzo[d]thiazol-2-yl; when X is 0, n is 1 and W is an optionally substituted pyridinyl, W' can not be an optionally substituted 2-pyridinyl; when X is CH 2 , n is 2 and W' is aryl, W can not be 4-imidazolyl.
WO 2005/123703 PCT/IB2005/002390 8 The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Definition of terms Listed below are definitions of various terms used in the specification and claims to describe the present invention. For the avoidance of the doubt it is to be understood that in this specification "C1-C6" means a carbon group having 1, 2, 3, 4, 5 or 6 carbons atoms. "Co-C 6 " means a carbon group having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. In this specification "C" means a carbon atom. In the case where a subscript is the integer 0 (zero) the group to which the subscript refers to indicates that the group is absent, i.e. there is a direct bond between the groups. In this specification, unless stated otherwise, the term "bond" is a saturated bond. In the above definition, the term "CI-C-alkyl" includes both straight and branched chain alkyl groups and may be groups such as methyl, ethyl, n-propyl, i propyl n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n hexyl, i-hexyl, t-hexyl or the like. In this specification, unless stated otherwise, the term "alkenyl" includes both straight and branched chain alkenyl groups. The term "C 2
-C
6 -alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, 1-propenyl, i-propenyl, 1-butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl, hexenyl and the like. In this specification, unless stated otherwise, the term "alkynyl" includes both straight and branched chain alkynyl groups. The term C 2
-C
6 -alkynyl having 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, ibutynyl, pentynyl, i-pentynyl, hexynyl and the like. The term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term "aryl" are phenyl, naphthyl, 1,2,3,4, tetrahydronaphthyl, indyl, indenyl and the like. In this specification, unless stated otherwise, the term "halo" or "halogen" may be fluoro, chloro, bromo or iodo. In this specification, unless stated otherwise, a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0, or S, includes WO 2005/123703 PCT/IB2005/002390 9 aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated. Example of such rings may be, but are not limited to furyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl, triazolyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclohexenyl, cyclopentyl and the like. In this specification, unless stated otherwise, the term "alkylaryl", "alkylheteroaryl" and "alkylcycloalkyl" refer to a substituent that is attached via the alkyl group to an aryl, heteroaryl and cycloalkyl group. The term "C1-C 6 -alkylaryl" includes aryl-Ci-C-alkyl group such as benzyl group, 1-phenylethyl group, 2 phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-naphthyhnethyl group, 2-naphthylmethyl group or the like. The term "C 1
-C
6 alkyheteroaryl" includes heteroaryl-C 1
-C
3 -alkyl group, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2 furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group, 3-thienyhnethyl group, 1-imidazolylmethyl group, 2-imidazolylmethyl group, 2-thiazolyhnethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 1-quinolylmethyl group or the like. In this specification, unless stated otherwise, the term "alkylhalo" means an alkyl group as defined above, substituted with one or more halogen. The term "C 1
-C
6 alkylhalo" may include, but not limited to fluoroethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, bromoethyl and the like. The term "O-C 1 C 6 -alkylhalo" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy-and the like. In the specification, unless stated otherwise, the term "heteroaryl" refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least on heteroatom selected independently from 0, N or S to form a ring such as furyl (furan ring), benzofuranyl (benzofaran), thienyl (thiophene), benzothiophenyl (benzothiophene), oxadiazolyl (oxadiazole ring), pyrrolyl (pyrrole ring), imidazolyl (imidazole ring), pyrazolyl (pyrazole ring), thiazolyl (thiazole ring), isothiazolyl (isothiazole ring), triazolyl (triazole ring), tetrazolyl (tetrazole ring), pyridil (pyridine ring), pyrazynyl (pyrazine ring), pyrimidinyl (pyrimidine ring), pyridazinyl (pyridazine ring), indolyl (indole ring), isoindolyl (isoindole ring), benzoimidazolyl (benzimidazole ring), purinyl group (purine ring), quinolyl (quinoline ring), phtalazinyl (phtalazine ring), naphtyridinyl (naphtyridine ring), quinoxalinyl (quinoxaline ring), cinnolyl (cinnoline ring), pteridinyl (pteridine ring), oxazolyl (oxazole ring), isoxazolyl (isoxazole ring), benzoxazolyl (benzoxazole ring), benzothiazolyl (benzothiaziole ring), furazanyl (furazan ring), benzotriazolyl (benzotriazol ring), imidazopyridinyl (imidazopyridine ring), pyrazolopyridinyl (pyrazolopyridine ring), and the like. In this specification, unless stated otherwise, the term "heterocycle" refers to an optionally substituted, mono cyclic or bicyclic saturated, partially saturated or unsaturated ring system containing at least one heteroatom selected independently from N, O or S.
WO 2005/123703 PCT/IB2005/002390 10 In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted carbocycles containing no heteroatoms, includes mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include on ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo fused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene and the like. The term "(C3-C 7 )cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl and the like. "Solvate" refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of formula I) and a solvent. The solvent is a pharmaceutically acceptable solvent as water preferably; such solvent may not interfere with the biological activity of the solute. In this specification, unless stated otherwise, the term "optionally substituted" refers to radicals further bearing one or more substituents which may be, but are not limited to, hydroxyl, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amido, amidine, carboxyl, carboxamide, carbamate, ester, sulfonyl, sulfonamide, and the like. Preferred compounds of the present invention are compounds of formula II depicted below II Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from a group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group cf formula: WO 2005/123703 PCT/IB2005/002390 11 R2 R 2
R
2 R' R 1 R R 1 O R 3 -N R R 2 jR2j< R N ~~N >s >, R' R- R 2 R N R RR
R
2 R2 R 2 R
R
3 RR N R R 2 R N R2 N ~ RN 3 N- R2 N NRN N~<
R
2
R
1
R
2
R
1 RR RN - -Z 33Z RR R R N R W - A I 1 R4 N R3- RN3NN R3' N Z>A R, R2, RA, R 4 , R and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1
-C
6 -alkyl, Cr-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-Cr-C 6 -alkyl, 0-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C 3
-C
6 alkenyl, 0.-C 2
-C
6 -alkyl-OR 6 , O-C 3
-C
7 -cycloalky1, 0-CrjC 6 -alkyl heteroaryl, O-Cr-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3
-C
7 -cyc1oalkyl, C 3 C 7 -cycloalkyl-Cr-C 6 -alkyl, 0-C 3
-C
7 -cycloalkyl-Cr-C 6 -alkyl, 0 heteroaryl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, 0-aryl, Cr-C 6 alkylaryl, Cr3C 6 -alkylhalo-OR 6 , CrC 6 -alkynyl-OR 6 , C 3 -C-alkenyl OR, Co-C 6 -alkyl-S-R , 0-C 2
-C
6 -alkyl-S-R, Co-C 6 -alkyl-S(=O)-R, 0
C
2
-C
6 -alkyl-S(=0)-R , Co-C 6 -alkyl-S(=o) 2
-R
6 , O-CrC6-alkyl-S(=o)2 R , Co-C 6 -alkyl-NR R, 0-C 2
-C
6 -alkyl-NRR, Co-C 6 -alkyl
S(=O)
2
NR
6
R
7 , Co-C 6 -alkyl-NR 6
-S(=O)
2
R
7 , O-Ci-CC 6 -alkyl S(=0) 2 NR6R7, -O-CC 6 -alkyl- -S(=0) 2 R7, Co-C 6 -alkyl-C(=O)
NR
6
R
7 , C-C 6 -alCyl-NR 6
C(=O)-R
7 , -CrC 6 -alkyl-C(=O)-NR 6
R
7 , 0
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , Co-C 6 -alkyl-OC(=)-R , Co-C-alkyl C(=O)-OR6, 0-C 2 -C(=lO)-R6 O-C 6 -aIkyl-C(=O)-OR , Co-C 6 -alkyl-C(=O)-R 6 , O-CrC 6 -alkyl-C(=0)-R 6 , Co-C 6 -alkyl-NR 6 C(=0)-OR 7 , Co-C 6 -alkyl-O-C(=0)-NR 6
R
7 or Co-C 6 -alkyl-NR 6 -C(=0)
NR
7
R
8 substituents; wherein optionally two sub stituents are combined to the intervening atoms to form a bicycle aryl, cycloailkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CC-alkyl, CrC 6 -alkylhalo, C 2 -C6-alkynyl, C 2
-C
6 alkenyl, 0-C 1
C
6 -alkyl, 0-C C 6 -alkylhalo, O-C 3
-C
6 -alkyny1, O-Crl alkenyl, -C 3
-C
7 -cycloalkyl, O-Cr-C 6 -alkyl-heteroaryl, O-CrC 6 alkylaryl, CrC 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CrC alkyl, o-C 3
-C
7 -cycloalkyl-CeC,-alkyl, 0-heteroaryl, heteroaryl, Cr
C
6 -alkyl-heteroaryl, aryl, 0-aryl; WO 2005/123703 PCT/IB2005/002390 12
R
6 , R 7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Z1, Z2, Z3, Z4, Z , Z6, Z 7 and ZI are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by I to 5 A m groups; m is an integer from I to 5; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, C-C 6 -alkyl-0,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-O, C 3
-C
6 -alkynyl-0, C 3
-C
6 -alkenyl-0, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=0), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6
-NR
9 S(=0) 2 ,
CC-C
6 -alkyl-S(=0) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=O), Co-C 6 -alkyl-OC(=0), Co-C 6 -alkyl-C(=0)-O, Co-C 6 -alkyl C(=O), CO-C 6 -alkyl-NR 9 -C(=0)-O, Co-C 6 -alkyl-O-C(=0)-NR 9 , CO-C 6 alkyl-NR 9
-C(=O)-NR
10 , Co-C 6 -alkyl-NR 9
-C(=NR
10 )NR, Co-C 6 -alkyl
(C=NR
9 )NR, Co-C 6 -alkyl-C(=0)-0-C-C 6 -alkyl, Co-C 6 -alkyl-C(=0)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents;
R
9 , R" 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyL, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; W' denotes a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0 and S, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0 and S, provided that W' is a aryl, heteroaryl or heterocycle selected from the group of formula: WO 2005/123703 PCT/1B20051002390 13 0 GqGq* qB B1 qN %S\ N Gq 0 N 0 G% 0 O-B' G0 NZ'Ia N 1-L
.
N '-C Gq-~; -- oG KI B ~-. ~j>~ ~N - N KB2 N N SN. 0 Gq N Gq N >-0 G Ne . NG N) 0 0 Gq Gq- Z \ GZ j NO0 6' Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C,-C 6 alkyl, C,-C 6 -allcylhalo, C 2
-C
6 -allcynyl, C 2 -0 6 -alkenyl, O-C,-C 6 -alkyl,
O-C,-C
6 -allcylhalo, O-C 3
-C
6 -alkYnyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR1 2 , O-C 3
-C
7 -CYCloalcyl, O-Cl-C 6 -alkyl-heteroaryl, O-Cl-C6 alkylaryl, CO-C 6 -alkyl-0R' 2 , C 3
-C
7 -CYCloalkYl, C 3
-C
7 -CYCloalkYl-C 1 C 6 -alkYl, O-C 3
-C
7 -cycloalkyl-C1-C 6 -alkYl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, 0-aryl, Cl-C 6 -alkylaryl, CI-C 6 -alkylhalo OR 1, C 3
-C
6 -alkynyl-OR 1 2 , C 3
-C
6 -alkenyl-OR 2, Cu-C 6 -alkCyl-S-R 2, 0
C
2
-C
6 IakY1-S-R , C 0
-C
6 -alkYl-S(=O)-R' 2 , O-C 2
-G
6 -allcyl-S(=O)-R 12 ,
CO-C
6 -alkyl-S(=O) 2 -R'1 2 , O-Cl-C 6 -alkyl-S&O0) 2 -R'1 2 , Co-.C 6 -alkyl i\TR1 2
R'
3 , O-C 2
-C
6 alklvl-R2R 3,C0-C 6 -alkCYl-S(=O) 2 NR 12R 3,CO-C 6 alkyl-NR1 2
S(=O)
2 R 13 , O-Cl-C 6 -alkyl-S(=O) 2 NR1 2 R 1 3 , O-C 2
-C
6 -alkyl NP. 12S(=O) 2 R 13 , CO-C 6 -alkyl-C(=O)-NR 12R3, CO-.C 6 -alkyl
NR
2 C(= O)-R'1 3 , O-C,-C 6 _alkylC(=O)_NR 1 2
R
13 , O-C 2
-C
6 -alkYl
NR'
2
C(=O)_R
3 , C0-C 6 -alkyl-OC(=O)-R' 2 , CO-C 6 -alkyl-C&=O)-0R 2 , O-C .
2
-C
6 -alkyl-OC(=O)-R'1 2 , O-C1-C 6 -alkyl-C(=O)-OR 1 2 , Co-C 6 -alkyl C(0)-R 1 2 , O-C 1
-C
6 -akyl-C=O)-R 1 2 , CO-C 6 -alkyl-NR' 2
-C(=O)-OR'
3 ,
CO-C
6 -alky-O-C(=O)-NR 12R 13or CO-C 6 -alkyl-NR 2 -C(=O)-.NR3 R 1 sub stituents; wherein optionally two sub stituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or WO 2005/123703 PCT/IB2005/002390 14 heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C-C 6 -alkyl, O-Cl-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C 1
-C
6 alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, O-C 3
-C
7 cycloalkyl-C 1
-C
6 -alkyl, 0-heteroaryl, heteroaryl; CI-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from I to 5; R", R13 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; Z9, Z10, Z11, z12, Z 13, Z 14, Z15, Z16 and Z7 are each independently selected from the group consisting of -C=, -C=C-, -C(=O)-, -C(=S)-, C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 G4 groups; B1, B2 and B 3 are each selected independently from the group consisting of C, C=C, C=N, S, 0 or N which may further be substituted by one G4 group; Any N may be an N-oxide; provided that: when X is independently selected from NR 5 , 0, S or an optionally substituted C-C 6 -alkyl, W is an optionally substituted 2-pyridinyl and R1 5 is independently selected from hydrogen, an optionally substituted
C
1
-C
6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl heteroaryl or aryl, W' can not be an optionally substituted aryl; when X is 0 and W' is an optionally substituted aryl or heteroaryl, W can not be an optionally substituted 3-pyridazinyl or 4-pyrimidinyl; when X is CH 2 and W' is aryl, W can not be 2-phenyloxazol-4-yl, 4 phenyloxazol-2-yl, 4-(3-(benzyloxy)propyl)-oxazol-2-yl, 4 phenylthiazol-2-yl, 4-methylthiazol-2-yl or benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl; when X is 0 and W is an optionally substituted pyridinyl, W' can not be an optionally substituted 2-pyridinyl; when X is CH 2
CH
2 and W' is aryl, W can not be 4-imidazolyl.
WO 2005/123703 PCT/IB2005/002390 15 The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. More preferred compounds of the present invention are compounds of formula 1-A depicted below Z1 Z13'Z 4-Z15 z1,-z12 Zz1 717 Gq II-A Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R2 R2 Ra
SR
3 -N R2 1 R2 R I S 0,R N - - I,>- R2-N R1~< RJN R2 R 2
R
2 R
R
3 R' RN R N 3 N 1 JR > N/ S ~ N ~ R 3 R N-0'
R
2 R R 2
R
1 R 1R 3 R/N-_R R 2 N R2~ N R1. R4 N N N R 3 N R3 N
R
5
R
5 R4 A
R
1 , R 2 , R3, R 4 , R 5 and A'" are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Cr-C 6 -alkyl, Cr-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, 0-Cr-C 6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C 3
-C
6 alkenyl, 0-C 2
-C
6 -alkyl-OR 6 , O-C 3
-C
7 -cycloalkcyl, 0-Cr-C 6 -alkyl - heteroaryl, 0-CrC 6 -alkylary1, Co-C 6 -alkyl-OR 6 , C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-Cr-C 6 -alkyl, O-C 3
-C
7 -cycloalkyl-Cr-C 6 -alky1, 0 heteroaryl, heteroaryl, Cr C 6 -alkyl-heteroaryl, aryl, 0-aryl, Cr-C 6 alkylaryl, CrCs-alkyhalo-OR , C 3
-C
6 -alkynyl-OR , C 3 -C-alkenyl- WO 2005/123703 PCT/IB2005/002390 16 OR', Co-C 6 -alkyl-S-R 6 , O-C 2
-C
6 -alkyl-S-R', CO-C 6 -alkyl-S(=O)-R 6 , O
C
2
-C
6 -alkyl-S(=O)-R6, Co-C 6 -alkyl-S(=0) 2 -R6, O-C-C 6 -alkyl-S(=0) 2 R 6 , Co-C 6 -alkyl-NR6 R, 0-C 2
-C
6 -alkyl-NR 6
R
7 , Co-C 6 -alkyl S(=0) 2
NRR
7 , Co-C 6 -alkyl-NR 6
-S(=O)
2
R
7 , O-C-C 6 -alkyl
S(=O)
2
NR
6
R
7 , O-Ci-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O) NR R7, Co-C 6 -alkyl-NR 6
C(=O)-R
7 , O-C1-C 6 -alkyl-C(=0)-NRR 7 , 0
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl C(=O)-OR , 0-C 2
-C
6 -alkyl-OC(=O)-R 6 , O-CrC 6 -alkyl-C(=O)-OR 6 , Co-C 6 -alkyl-C(=0)-R 6 , O-Cr-C 6 -alkyl-C(=O)-R, Co-C 6 -alkyl-NR 6 C(=O)-OR 7 , Co-C 6 -alky1-O-C(=O)-NR 6
R
7 or Co-C 6 -.alkyl-NR 6 -C(=0)
NR
7 R' substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C 1
-C
6 -alkyl, O-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C 1
-C
6 alkylaryl, Ci-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CI-C 6 alkyl, O-C 3
-C
7 -cycloalky-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C 6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted CI-C 6 -alkyl, CI-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-CI-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, C-C 6 -alkyl-O,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C 1
-C
6 alkylhalo-O, C 3
-C
6 -alkynyl-O, C 3
-C
6 -alkenyl-0, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6
-NR
9 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=0)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR-C(=O)-NR1', Co-C 6 -alkyl-NR 9
-C(=NR'
0 )NR', Co-C 6 -alkyl
(C=NR
9 )NR'U, Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R?, R 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7
-
WO 2005/123703 PCT/IB2005/002390 17 cycloalky-C-C 6 -alkyl, heteroaryl, CI-C 6 -alkyl-heteroaryl, aryl, heterocycle; 9 10 11 1 3 1 5 1 Z,Z Z z1, z1, Z 4, Z11, Z16 and Z' are each independently selected from the group consisting of -C=, -C=C-, -C(=O)-, -C(=S)-, -C-, -0-, -N=, -N or -S- which may further be substituted by 1 to 5 Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, Ci-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl,
O-C-C
6 -allcylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR" O-C 3 -C-cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Co-C 6 -alkyl-OR 12 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Cr
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, O-heteroaryl, heteroaryl,
C-C
6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo
OR'
2 , C 3
-C
6 -alkynyl-OR 12 , C 3
-C
6 -alkenyl-OR 2 , CO-C 6 -alkyl-S-R 2 , O 12121
C-C
6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R , O-C 2
-C
6 -alkyl-S(=O)-R, Co-C 6 -alkyl-S(=0) 2
-R
12 , O-C-C 6 -alkyl-S(=0) 2
-R
2 , Co-C 6 -alkyl NR R3, O-C 2
-C
6 -alkyl-NR 2 R 13 , Co-C 6 -alkyl-S(=O)2NR 2 R", Co-C 6 alkyl-NR' 2 -S(=0) 2 R", O-C-C 6 -alkyl-S(=0) 2
NR'
2 R1 3 , O-C 2
-C
6 -alkyl
NR
2
-S(=O)
2 R 1, Co-C 6 -alkyl-C(=O)-NR 2 R 13 , Co-C 6 -alkyl
NR
2
C(=O)-R
13 , O-CI-C 6 -alkyl-C(=O)-NR R", O-C 2
-C
6 -alkyl
NR'
2 C(=O)-R, C-C6-alkyl-OC(=0)-R 12 , Co-C6-alkyl-C(=O)-OR 2 ,
O-C
2
-C
6 -alkyl-OC(=O)-R 12 , O-CI-C 6 -alkyl-C(=O)-OR 2 , Co-C 6 -alkyl
C(=O)-R'
2 , O-Cr-C 6 -alkyl-C(=O)-R 2 , Co-C 6 -alkyl-NR1 2 -C(=O)-OR1 3 , _NR1213 R2_C(O)_N13p 14 Co-C 6 -alkyl-O-C(=O)-NR'R' or Co-C 6 -alkyl-NR 2 -C(=O)-NR R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, Cj-C 6 -alkylhalo, C 2 -C6-alkynyl, C 2
-C
6 alkenyl, O-C-C 6 -alkyl, O-Cl-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C3-C6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-Cl-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, O-C 3
-C
7 cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cr-C 6 -alkyl heteroaryl, aryl, O-aryl; q is an integer from 1 to 5; 12 13 R , R13 and R' 4 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, CI-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -Cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
WO 2005/123703 PCT/IB2005/002390 18 In one aspect, the compounds of the present invention are represented by Formula II-A wherein the heterocyclic ring system is specified as in the formula II Al depicted below W -B 3
B
1 B G N B 2 II-Al Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R 2 R 2 R1 1 Rs R1-~ R
R
3 -N R2 R2 R >I s .<R I N N.
0 R1 I ~ s{R 1 R 21 R- R1N l 2 N R 3 N N2N N N N R2 R 2 R 2
R
1
R
3
R
1 3 3 R R2 R2 N R IN N""' N l Fl 4 NN.NjF 3
NR
3 NA F 3
R
2
R
1 R2 R1 R' 3l R4. N Z3N- Z2- Z2
R
5
R
5
R
4
A
m R', R2, R, R4, R5 and A m are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C 1
-C
6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 2
-C
6 -alkyl-OR 6 , O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C-alkyl-OR6, C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, 0-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl 0-aryl, C-C 6 alkylaryl, C-C 6 -alkylhalo-OR 6 , C 3
-C
6 -alkynyl-0R, C 3 -C6-alkenyl OR', Co-C 6 -alkyl-S-R 6 , O-C 2
-C
6 -alCyl-S-R 6 , Co-C 6 -alkyi-S(=O)-R 6 0
C
2
-C
6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=0) 2
-R
6 , O-C-C 6 -alkyl-S(=0) 2 R6, Co-C 6 -alkyl-NR 7, O-C 2
-C
6 -alyl-NR 6
R
7 , Co-C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 19
S(=O)
2
NR
6
R
7 , CO-C 6 -alkyl-NR 6 -S(=0)2R 7 , O-CI-C 6 -alkyl S(=0) 2 NR6R7, O-C-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O)
NR
6
R
7 , Co-C 6 -alkyl-NR 6
C(=O)-R
7 , O-C-C 6 -alkyl-C(=O)-NR 6
R
7 , 0
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl C(=O)-OR6, O-C 2
-C
6 -alkyl-OC(=0)-R6, O-C,-C 6 -alkyl-C(=O)-OR6 Co-C 6 -alkyl-C(=0)-R, O-C 1
-C
6 -alkyl-C(=O)-R6, Co-C 6 -alkyl-NR 6 _
C(=O)-OR
7 , Co-C 6 -alkyl-O-C(=O)-NR6R' or Co-C 6 -alkyl-NR 6
-C(=O)
NR
7 R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C 1
-C
6 -alkyl, O-Ci-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-Cr-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, C-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Ci-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl;
R
6 , RW and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted Cr-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-Cl-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; ZI, Z2, Z3, Z4, Z , Z6, Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 Am groups; m is an integer from 1 to 5; X is selected from an optionally substituted Cl-C 6 -alkyl, C 1
-C
6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-CI-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, CI-C 6 -alkyl-O,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, Cr-C 6 alkylhalo-O, C 3
-C
6 -alkynyl-O, C 3
-C
6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0)2, Co-C 6 -alkyl-NR 9 , Co-C 6
-NR
9 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR9, Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=0), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=0)-NR" 0 , Co-C 6 -alkyl-NR 9
-C(=NR"
0 )NR", Co-C 6 -alkyl
(C=NR
9
)NR'
0 , Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR) or Co-C 6 -alkyl-O-N=CR 9 substituents;
R
9 , R 10 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted Cl-C 6 -alkyl, C 1
-C
6 alkyihalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalky-C 1
-C
6 -alkyl, . heteroaryl, CI-C 6 -alkyl-heteroaryl, aryl, heterocycle; WO 2005/123703 PCT/IB2005/002390 20 B' and B 2 are each selected independently from N or C which may further be substituted by Gq groups; B 3 is selected independently from C, C=C, C=N, S, 0 or N which may farther be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-CI-C 6 -alkyl,
O-C-C
6 -alkylhalo, 0-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR, O-C-C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-Cl-C 6 alkylaryl, Co-C 6 -alkyl-OR 2 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-Ci-C 6 -alkyl, 0-heteroaryl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl, 0-aryl, CrQ-aklaryl, C-C 6 -alkylhalo OR 12, C-C 6 -alkynyl-OR , C 3
-C
6 -alkenyl-OR' , Co-C 6 -alkyl-S-R , O
C
2
-C
6 -alkyl-S-R , Co-CG-alkyl-S(=O)-R1 2 , O-C 2
-C
6 -alkyl-S(=O)-R, Co-C 6 -alkyl-S(=O) 2
-R
2 , O-C-C 6 -alkyl-S(=O) 2
-R
2 , Co-C 6 -alkyl NR R , O-C 2
-C
6 -alkyl-NR R", Co-CR-alkyl-S(=0)2NR R3, Co-C 6 alkyl-NR 2 -S(=0) 2
R
13 , O-CI-C 6 -alkyl-S(=0) 2
NR
12 R1', O-C 2
-C
6 -alkyl NR1 2
-S(=O)
2
R
3 , Co-C 6 -alkyl-C(=O)-NR 2 R 13 , Co-C 6 -alkyl
NR
12
C(=O)-R
3 , O-C-C 6 -alkyl-C(=0)-NR 12
R
3 , O-C 2
-C
6 -alkyl NR1 2
C(=O)-R'
3 , Co-C 6 -alkyl-OC(=O)-R 2 , Co-C 6 -alkyl-C(=O)-OR 12 ,
O-C
2
-C
6 -alkyl-OC(=O)-R , O-C-C6-alkyl-C(=0)-OR', Co-C 6 -alkyl
C(=O)-R
2 , O-C-C 6 -alkyl-CQ=O)-R 2 , Co-C 6 -alkyl-NR1 2
-C(=O)-OR
13 , Co-C 6 -alkyl-O-C(=O)-NR 2 R' or Co-C 6 -alkyl-NRi-C(=O)-NR1 3 R14 substituents; q is an integer from 1 to 5; R , R" and R 14 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a second aspect, the compounds of the present invention are represented by Formula II-A wherein the heterocyclic ring system is specified as in the formula II A2 depicted below WO 2005/123703 PCT/IB2005/002390 21 WN G II-A2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R2 RR2 RR2
S
1 0 NN1' R x-R 1 RR xN R2 R N
R
3
R
1 R2-N R R R0 NC NN R 'NA R N~/ N
R
2 2 RiR2 R
R
3 RN R N R N-0 -1 -zzi 3-C > N VNm Y ~ R R R R R1 2 3 4 5 R, R, R, R, R and A m are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Ci-C 6 -alkyl, C1-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C1-C 6 -alkyl, 0-C1-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C 3
-C
6 alkenyl, 0-C 2
-C
6 -alkcyl-OR 6 , -C 3
-C
7 -cycloalkyl, O-C1-C 6 -alkyl heteroaryl, 0-Ci-C 6 -alkylaryl, Co-C 6 -alkyl-OR, C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C 1
-C
6 -alkyl, 0-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0 heteroaryl, heteroaryl, Ci-C-alkyl-heteroaryl, aryl, 0-aryl, C 1
-C
6 alklaryl, C2-C 6 -alkylhalo-OR 6 , C 3
-C
6 -alkynyl-OR 6 , C 3
-C
6 -alkenyl OR , Co-C 6 -alkyl-S-R, O-C 2
-C
6 -alkyl-S-R6, Co-C 6 -alkyl-S(=0)-R 6 , 0
C
2 -C6-alkyl-S(=0)-R 6 , Co-C 6 -alkyl-S(=0) 2
-R
6 , O-C 1
-C
6 -alkyl-S(=0) 2 R 6 , Co-C 6 -alkyl-NR 6
R
7 , O-C 2
-C
6 -alkyl-NRR 7 , Co-C 6 -alkyl
S(=O)
2
NR
6
R
7 , Co-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , O-C1-C6-alkyl S(=0) 2
NR
6
R
7 , O-C 1
-C
6 -alkyl-NR6-S(=O) 2
R
7 , Co-C 6 -alkyl-C(=O)- WO 2005/123703 PCT/IB2005/002390 22
NR
6
R
7 , Co-C 6 -alkyl-NR 6
C(=O)-R
7 , O-C 1
-C
6 -alkyl-C(=O)-lNR 6
R
7 , 0 Cr-C 6 -alkyl-NR 6
C(=O)-R
7 , Co-C-alky-OC(=0)-R 6 , Co-C 6 -alkyl C(=O)-OR6, O-C 2
-C
6 -alkyl-OC(=0)-R', O-C1-C 6 -alkyl-C(=O)-OR', Co-C 6 -alkyl-C(=O)-R 6 , O-C-C 6 -alkyl-C(=0)-R6, Co-C 6 -alkyl-NR6
C(=O)-OR
7 , Co-C6-alkyl-O-C(=0)-NR 6
R
7 or Co-C 6 -alkyl-NR 6 -C(=0)
NRR
8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, 0-C-C 6 -alkyl, 0-CI-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C3-C6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-Cl-C 6 -alkyl-heteroaryl, O-CI-C 6 alkylaryl, C 1
-C
6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C 1
-C
6 alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, O-aryl;
R
6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted Cl-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkCnyl, C 3
-C
7 -cycloalkyl, C3-C7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A! m groups; m is an integer from 1 to 5; X is selected from an optionally substituted Cl-C 6 -alkyl, C-C 6 -alkylhalo,
C
2 -C6-alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, 0-C-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, 0-C 3
-C
7 -cycloalkyl, C-C 6 -alkyl-O,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyL, S-Co-C 6 -alkyl, CI-C 6 alkylhalo-0, C 3
-C
6 -alkynyl-0, C 3
-C
6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6
-NR
9 S(=0) 2 , Co-C 6 -alkyl-S(=O) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=O), CO-C 6 -alkyl-OC(=0), Co-C 6 -alkyl-C(=0)-O, Co-C 6 -alkyl C(=0), Co-C 6 -alkyl-NR 9 -C(=O)-0, Co-C 6 -alkyl-O-C(=0)-NR 9 , Co-C 6 alkyl-NR-C(=O)-NR 0 , Co-C 6 -alkyl-R 9 -C(=NR")NR", Co-C 6 -alkyl
(C=NR
9 )NR ', Co-C 6 -alkyl-C(=0)-O-Co-C 6 -alky, Co-C 6 -alkyl-C(=O)
NR
9
-CO-C
6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R', R" and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkcy-C 1
-C
6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1
-C
6
-
WO 2005/123703 PCT/IB2005/002390 23 alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-CI-C 6 -alkyl,
O-C-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, 0-C 2
-C
6 -alkyl
OR
12 , O-C 3
-C
7 -cycloalkyl, O-Cr-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Co-C 6 -alkyl-OR 2 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, O-aryl, CrC 6 -alkylaryl, CI-C 6 -alkylhalo OR", C 3
-C
6 -alkynyl-OR' 2 , C 3
-C
6 -alkenyl-OR' 2 , Co-C 6 -alkyl-S-R1 2 , 0 C-C-alkyl-S-R 2 , CO-C6-alky1-S(=O)-R 2, O-C 2
-C
6 -alkyl-S(=O)-RI 2 , Co-C 6 -alkyl-S(=0) 2
-R'
2 , O-C-C 6 -akyl-S(=O),-R 2 , Co-C 6 -alkyl NR2R", O-C 2
-C
6 -alkyl-NR' 2 R, Co-C 6 -alkyl-S(=O) 2 NR2R", Co-C6 alkyl-NR-S(=O) 2 R1 3 , O-C-C 6 -alkyl-S(=0) 2 NR R 1, O-C 2
-C
6 -alkyl NR1 2 -S(=0) 2
R
3 , Co-C 6 -alkyl-C(=O)-NR R , Co-C 6 -alkyl
NR
2 C(=O)-R 1, O-C-C 6 -alkyl-C(=O)-NR 2 R", O-C 2
-C
6 -alkyl NR C(=O)-R, Co-C 6 -alkyl-OC(=O)-R , Co-C 6 -alkyl-C(=O)-OR1,
O-C
2
-C
6 -alkyl-OC(=O)-R1 2 , O-C-C 6 -alkyl-C(=O)-OR 12 , Co-C 6 -alkyl
C(=O)-R
2 , O-C-C 6 -alkyl-C(=O)-R' 2 , Co-C 6 -alkyl-NR' 2
-C(=O)-OR
3 , Co-C 6 -alkyl-O-C(=O)-NR 12
R
13 or Co-C 6 -alkyl-NR' 2 -C(=O)-NR1 3
R"
4 substituents; q is an integer from I to 5; 12 13 1 R , R and R 14 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, Cr-C6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-Ci-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a more preferred aspect of Formula II-A2, the compounds of the invention are represented by Formula II-A2-a R2 R1 R 3 NG X -Gq N X II-A2-a Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein
R
1 , R 2 , R 3 and Ri are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1
-C
6
-
WO 2005/123703 PCT/IB2005/002390 24 alkyl, Cl-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl,
O-CI-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl
OR
5 , O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 -alkylaryl,
C
0
-C
6 -alkyl-OR, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Cr-C 6 -alkyl, 0
C
3
-C
7 -cycloalkyl-CI-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl, 0-aryl, C 1
-C
6 -alkylaryl, Cr-C 6 -alkylhalo-OR, C 3
-C
6 alkynyl-OR 5 , C 3
-C
6 -alkenyl-OR 5 , Co-C 6 -alkyl-S-R 5 , O-C 2
-C
6 -alkyl-S
R
5 , Co-C 6 -alkyl-S(=O)-R, O-C 2
-C
6 -alkyl-S(=O)-R 5 , Co-C 6 -alkyl
S(=O)
2 -R, O-CI-C 6 -alkyl-S(=O) 2
-R
5 , Co-C 6 -alkyl-NRR6, O-C 2
-C
6 alkyl-NR R, Co-C 6 -alkyl-S(=0) 2
NRR
6 , Co-C 6 -alkyl-NR 5
-S(=O)
2
R
6 ,
O-C-C
6 -alkyl-S(=0) 2 NR5 R, O-C 2
-C
6 -alkyl-Nk 5
_S(=O)
2
R
6 , Co-C 6 alkyl-C(=0)-NR 5 R 6 , Co-C 6 -alkyl-NR 5
C(=O)-R
6 , O-Cr-C 6 -alkyl
C(=O)-NR
5
R
6 , O-C 2
-C
6 -alkyl-NR 5
C(=O)-R
6 , Co-C 6 -alIkyl-OC(=O)-R, Co-C 6 -alkyl-C(=O)-OR 5 , O-C 2
-C
6 -alkyl-OC(=O)-R, O-C 1
-C
6 -alkyl
C(=O)-OR
5 , Co-C 6 -alkyl-C(=0)-R 5 , O-C-C 6 -alkyl-C(=O)-Rs, Co-C 6 alkyl-NR'-C(=O-OR6, Co-C 6 -alkyl-O-C(=O)-NRR6 or Co-C 6 -alkyl
NR
5 -C(=O)-NR R7 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-Cy-C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C 1
-C
6 alkylaryl, CI-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, O-aryl;
R
5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, Cr-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-CI-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; X is selected from an optionally substituted Cl-C 6 -alkyl, C 1
-C
6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, 0-C 3
-C
6 -alkenyl, 0-C 3
-C
7 -cycloalkyl, C-C 6 -alkyl-O,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-O, C 3
-C
6 -alkynyl-O, C 3
-C
6 -alkenyl-O, Co-C-alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkl-S(=O) 2 , Co-C 6 -alkyl-NR', Co-C 6 -NR'S(=0) 2 ,
CO-C
6 -alkyl-S(=0) 2 NR, Co-C 6 -alkyl-C(=O)-NR 8 , Co-C 6 -alkyl NRC(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=0), Co-C 6 -alkyl-NR-C(=0)-O, Co-C 6 -alkyl-O-C(=0)-NR 8 , Co-C 6 alkyl-NR-C(=O)-NR 9 , Co-C 6 -alkyl-NR 8
-C(=NR
9
)NR
0 , Co-C 6 -alkyl
(C=NRS)NR
9 , -Co-C 6 -alkyl-C(=O)-O-C-C 6 -alky, Co-C 6 -alkyl-C(=O) NR-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR) or Co-C6-alkyl-O-N=CR substituents;
R
8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, an optionally substituted Cr-C 6 -alkyl, CI-C 6
-
WO 2005/123703 PCT/IB2005/002390 25 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C3-C 7 -cycloalkyl, C 3
-C
7 cycloalky-Cl-C6-alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C6 alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl,
O-C-C
6 -alkylhalo, 0-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2 -C6-alkyl OR", O-C3-C 7 -cycloaIkyl, O-C-C 6 -alkyl-heteroaryl, 0-C-C6 alkylaryl, Co-C 6 -alkyl-OR1, C3-C 7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C
C
6 -alkyl, 0-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, CrC 6 -alkyl-heteroaryl, aryl, O-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo
OR
1 , C3-C 6 -alkynyl-ORD, C 3
-C
6 -alkenyl-OR", Co-C 6 -alkyl-S-R", 0
C
2
-C
6 -alkyl-S-R", Co-C 6 -alkyl-S(=O)-R", O-C 2
-C
6 -alkyl-S(=0)-R", Co-C-alkyl-S(=0) 2 -R"I, O-CI-C 6 -alkyl-S(=O) 2 -R", Co-C 6 -alkyl NR"R , O-C 2
-C
6 -alkyl-NR"R' 2 , Co-C 6 -alkyl-S(=O) 2 NR"R", Co-C 6 alkyl-NR 11
-S(&)
2
R
2 , O-C-C 6 -alkyl-S(=O) 2
NR
1 R 2 , O-C 2
-C
6 -alkyl NR"-S(=0) 2 R1 2 , Co-C 6 -alkyl-C(=O)-NR 1 1R 1 2, Co-C 6 -alkyl
NR
1 C(=O)-R , O-C-C 6 -alkyl-C(=O)-NR"R , O-C 2
-C
6 -alkyl NR'C(=O)-Rl 2 , Co-C-alkyl-OC(=O)-R", Co-C 6 -alkyl-C(=O)-OR1,
O-C
2
-C
6 -alkyl-OC(=O)-R' 1 , O-C-C 6 -alkyl-C(=O)-OR", Co-C 6 -alkyl C(=O)-R", O-C-C 6 -alkyl-C(=O)-R'1, Co-C 6 -alkyl-NR' -C(=O)-OR , Co-C 6 -alkyl-O-C(=O)-NRIIR or Co-C 6 -alkyl-NR1-C(=O)-NR R1 substituents; q is an integer from I to 5; R11 12 13 R , R and R are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, Cr-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalky1, C 3
-C
7 cycloalkyl-C-C6-alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a more preferred aspect of Formula II-A2-a, the compounds of the invention are represented by Formula II-A2-al R2 R 1 R4 N R ~NX N-Gq II-A2-al Or a pharmaceutically acceptable salt, hydrate or solvate of such compound WO 2005/123703 PCT/IB2005/002390 26 Wherein
R
1 , R2, R3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, CN, OH, an optionally substituted C 1
-C
6 -alkyl, C
C
6 -alkylhalo, Co-C 6 -alkyl-NRR 6 , Co-C 6 -alkyl-S(=0) 2
NR
5
R
6 , Co-C 6 alkyl-NRf-S(=0) 2
R
6 , Co-C 6 -alkyl-C=0)-NRR 6 , Co-C 6 -alkyl NRsC(=O)-R 6 , Co-C 6 -alkyl-OC(=O)-R 5 , Co-C 6 -alkyl-C(=O)-OR, Co
C
6 -alkyl-C(=O)-R 5 or Co-C 6 -alkyl-NR-C(=O)-NRR 7 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, Cj-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-CI-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C 1
-C
6 alkylaryl, CI-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C 1
-C
6 alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C 1 C 6 -alkyl-heteroaryl, aryl, O-aryl; R5, R6 and R7 are each independently selected from the group consisting of hydrogen, an optionally substituted C 1
-C
6 -alkyl, C 1
-C
6 alkylhalo, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, heteroaryl,
C-C
6 -alkyl-heteroaryl, aryl; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, O-Co-C 6 -alkyl, Co-Cs-alkyl-O, S-Co-C 6 -alkyl, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR, Co-C 6
-NR'S(=O)
2 , Co-C 6 -alkyl-S(=O) 2 NRi, Co-C 6 -alkyl-C(=O)-NR', Co-C 6 -alkyl NREC(=O), CO-C 6 -alkyl-C(=0)-O-C-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR8-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=0) or Co-C6-alkyl-NR-C(=0)-NR9 substituents;
R
8 and R 9 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 C 6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalky-C-C 6 alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, O-Cl-C6-alkyl, O-C-C 6 -alkylhalo, O-C 2
-C
6 alkyl-OR", O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR' 0 , C-C 7 -cyeloalkyl, C-C 7 -cycloalkyl-Cl
C
6 -alkyl, O-C-C 7 -cycloalkyl-C-C6-alkyl, 0-heteroaryl, heteroaryl,
C-C
6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR'", Co-C 6 -alkyl-S(=O)-R1 0 , 0-C 2
-C
6 -alkyl-S(=0)-R" 0 , Co-C 6 -alkyl
S(=O)-R
0 , O-Cj-C 6 -alkyl-S(=0) 2 -R1 0 , Co-C 6 -alkyl-NR R", O-C 2
-C
6 alkyl-NR' 0 R", C-C 6 -alkyl-S(=0) 2 NR1 0 R", Co-C 6 -alkyl-NR 10 S(=0) 2 Ru , O-C1-C 6 -alkyl-S(=0) 2
NR'
0 R', O-C 2
-C
6 -alkyl-NR' 0 S(=0) 2 R", Co-C 6 -alkyl-C(=O)-NR' 0 R", Co-C 6 -alkyl-NR1 0 C(=0)-R"1, WO 2005/123703 PCT/IB2005/002390 27
O-C-C
6 -aIkyl-C(=O)-NR 10 R", O-C 2
-C
6 -alkyl-NR 10
C(=O)-R
1 , CO-C 6 alkyl-C(=O)-R 0 , O-C-C 6 -alkyl-C(=O)-R 10 or Co-C 6 -alkyl-NR 0 C(=O)-NR" R 2 substituents; q is an integer from 1 to 5;
R
10 , R"' and R 2 are each independently selected from the group consisting of hydrogen, an optionally substituted CrC 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a more preferred aspect, the compounds of the present invention are represented by Formula II-A2-al wherein the linker is specified as in the formula II-A2-a2 depicted below R2 R R3 N jG4 R4 NN II-A2-a2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R', R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1
-C
6 -alkyl, C-C 6 alkylhialo or Co-C 6 -alkyl-NRR 6 substituents;
R
5 and R 6 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 3 C 7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl heteroaryl, aryl; groups are each independently selected from the group consisting of hydrogen, halogen, CN, an optionally substituted C-C 6 -alkyl, C 1
-C
6 alkylhalo, O-CO-C 6 -alkyl, O-Co-C 6 -alkylaryl, heteroaryl or aryl; q is an integer from 1 to 5; Any N may be an N-oxide; WO 2005/123703 PCT/IB2005/002390 28 The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a third aspect, the compounds of the present invention are represented by Formula II-A wherein the heterocyclic ring system is specified as in the formula II A3 depicted below x - -- Gq II-A3 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R 2 R 2 2R2 R R 1 N R' R 3 R R 3 -N R 2 -< . R N2< R < NSZ N $.N Ns R2R RR2 I R R R2 N P N R 2 N NI N N R2 R 2 RR
RR
3
R
1 R 3 Rs R 1 R 2 e i s R
N
2 NN R NNN 3 R3R N*'I.- RX NhI;
R
2 R1 1 R2 R 1 R
R
3
R
3
R
2 Z3 Z2Z 3 Z2 /I 4C> N4 R 4 N-~N R' No N\ZA R 5
R
5
R
4
A
t R1, R , R3, R , R5 and Am are each independently selected the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C6-alkyl, Cr-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, 0-C 1
-C
6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 2
-C
6 -alkyl-OR 6 , O-C 3
-C
7 -cycloalky O-Cl-C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 29 heteroaryl, O-C 1
-C
6 -alkylaryl, Co-C,-alkyl-OR 6 , C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C 1
-C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-Cr-C 6 -alkyL, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl O-aryl, Cr-C 6 alkylaryl, Ci-C 6 -alkylhalo-OR 6 , C 3
-C
6 -alkynyl-OR , C 3
-C
6 -alkenyl OR', Co-C 6 -alkyl-S-R 6 , 0-C 2
-C
6 -alkyl-S-R 6 , Co-C 6 -alkyl-S(=O)-R 6 , 0
C
2
-C
6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=0) 2
-R
6 , 0-C-C 6 -alkyl-S(=O) 2 R , Co-C6-alkyl-NRR 7 , O-C 2
-C
6 -alkyl-NR 6
R
7 , Co-C 6 -alkyl
S(=O)
2
NR
6
R
7 , Co-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , O-C-C 6 -alkyl
S(=O)
2 NR 6R7, O-C-C 6 -alkyl-NR6-S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O)
NRR
7 , Co-C 6 -alkyl-NR 6
C(=O)-R
7 , 0-C-C 6 -alkyl-C(=O)-NR 6
R
7 , 0
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , CC-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl C(=O)-OR6, O-C 2
-C
6 -alkyl-OC(=O)-R 6 , 0-C-C 6 -alkyl-C(=O)-OR6 Co-C 6 -alkyl-C(=O)-R 6 , O-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR C(=O)-OR, Co-C 6 -alkyl-O-C(=0)-NRR7 or Co-C 6 -alkyl-R -C(=O)
NR
7 R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, 0-C 3
-C
7 -cycloalkyl, O-Cr-C 6 -alkyl-heteroaryl, O-CI-C 6 alkylaryl, CI-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CI-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-Cj-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alky-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted Cr-C 6 -alkyl, Cr-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, 0-C-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, 0-C 3
-C
6 -alkenyl, 0-C 3
-C
7 -cycloalkyl, Co-C-alkyl-0,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C6-alkyl, C-C 6 alkylhalo-O, C 3
-C
6 -alkynyl-0, C 3
-C
6 -alkenyl-0, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C6-alkyl-S(=0)2, Co-C 6 -alkyl-NR 9 , Co-C 6 -NRS(=0) 2 , Co-C 6 -alkyl-S(=0) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=o), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=0), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9
-C(=O)-NR'
0 , Co-C 6 -alkYl-NR 9
-C(=NR
10 )NR", Co-C 6 -allcyl
(C=NR)NR
0 , Co-C 6 -alky-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; WO 2005/123703 PCT/IB2005/002390 30 R', R 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, CI-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3 -Cr-cycloalkyl, C 3
-C
7 cycloalky-C 1
-C
6 -alkyl, - heteroaryl, CI-C 6 -alkyl-heteroaryl, aryl, heterocycle; Bi represents independently C or N which may further be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl,
O-C-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3 -Cc-alkenyl, O-C 2
-C
6 -alkyl OR , O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Co-C 6 -alkyl-OR 2 , C 3 -Crcycloalkyl, C 3
C
7 cycloalkyl-C
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl,
C-C
6 -alkyl-heteroaryl, aryl, 0-aryl, C 1
-C
6 -alkylaryl, C-C 6 -alkylhalo OR , C 3
-C
6 -alkynyl-OR , C 3
-C
6 -alkenyl-OR , Co-C 6 -alkyl-S-R , O
C
2
-C
6 -alkyl-S-R 2 , Co-C 6 -alkyl-S(=O)-R 2 , O-C 2
-C
6 -alkyl-S(=O)-R12, Co-C 6 -alkyl-S(=O) 2
-R
2 , OCrC6-alkyl-S(=O)rR , Co-C 6 -alkyl NR R", 0-C 2
-C
6 -alkyl-NR' 2 R", Co-C 6 -alkyl-S(=O) 2
NR
2 R 13 , Co-C 6 alkyl-NR 2 -S(=0) 2
R
13 , O-CI-C 6 -alkyl-S(=O) 2
NR
2 R", O-C 2
-C
6 -alkyl
NR
12
-S(=O)
2
RI
3 , Co-C 6 -alkyl-C(=O)-NR 2 R", Co-C 6 -alkyl
NR
2
C(=O)-R
1 3 , O-C-C 6 -aLkyl-C(=0)-NR12 R 1, O-C 2
-C
6 -alkyl
NR
2 C(=O)-R", Co-C 6 -alkyl-OC(=0)-R1 2 , Co-C 6 -alkyl-C(=O)-OR 12 ,
O-C
2
-C
6 -alkyl-OC(=O)-R 2 , O-C-C 6 -alkyl-C(=O)-OR 12 , Co-C 6 -alkyl
C(=O)-R
2 , O-C-C 6 -alkyl-C(=O)-R 2 , Co-C 6 -alkyl-NRR 2
-C(=O)-OR
3 , Co-C 6 -alkyl-O-C(=O)-NR1 2 R1 3 or Co-C 6 -alkyl-NR 12 -C(=o)-NR R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C 1 C 6 -alkyl, C 1
-C
6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 alkyl, O-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 -alkylaryl, C 3
-C
7 cycloalkyl, C 3
-C
7 -cycloalkyl-CI-C 6 -alkyl, 0-C 3
-C
7 -cycloalkyl-C-C 6 alkyl, 0-heteroaryl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5;
R'
2 , R 13 and R1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; WO 2005/123703 PCT/IB2005/002390 31 The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a more preferred aspect of Formula II-A3, the compounds of the present invention are represented by Formula II-A3-a R23R
B
1 R 4~-N N --- G4 R 4~ II-A3-a Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R1, R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, CICs-alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3 -C6-alkynyl, O-C 3
-C
6 -alkenyl, 0-C 2
-C
6 -alkyl OR', O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CI-C 6 -alkyl, 0
C
3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl, 0-aryl, Ci-C 6 -alkylaryl, C-C 6 -alkylhalo-OR 5 , C 3
-C
6 alkynyl-OR 5 , C 3
-C
6 -alkenyl-OR 5 , Co-C 6 -alkyl-S-R 5 , O-C 2
-C
6 -alkyl-S
R
5 , Co-C 6 -alkyl-S(=O)-R 5 , O-C 2
-C
6 -alkyl-S(=O)-R 5 , Co-C 6 -alkyl S(=0) 2
-R
5 , O-C-C 6 -alkyl-S(=0) 2
-R
5 , CO-C 6 -alkyl-NRSR6, O-C 2
-C
6 alkyl-NRR 6 , Co-C 6 -alkyl-S(=0) 2 NRR , Co-C 6 -alkyl-NR 5
-S(=O)
2 R ,
O-C-C
6 -alkyl-S(=0) 2 NRs R, O-C 2
-C
6 -alkyl-NR-S(=0) 2
R
6 , Co-C 6 alkyl-C(=O)-NRR 6 , Co-C 6 -alkyl-NR 5
C(=O)-R
6 , O-Cl-C 6 -alkyl
C(=O)-NR
5
R
6 , O-C2-C6-kyl-NR 5 C(=O)-R, Co-C 6 -alkyl-OC(=O)-R, Co-C 6 -alkyl-C(=O)-ORs, 0-C 2
-C
6 -alkyl-OC(=O)-R 5 , O-CI-C 6 -alkyl C(=O)-OR', Co-C 6 -alkyl-C(=0)-R 5 ,. O-Cr-C 6 -alkyl-C(=O)-R 5 , Co-C 6 alkyl-NR-C(=O)OR , Co-C 6 -alkyl-O-C(=O)-NR 5 R6 or Co-C 6 -alkyl
NR
5 -C(=O)-NR R7 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-Cl-C6-alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, C-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalky-Cr-C 6 alkyl, O-C3-C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl; WO 2005/123703 PCT/IB2005/002390 32 R5, .R and R7 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-Cl-C6-alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; X is selected from an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-Cr-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, Co-C 6 -alkyl-O,
C
3 -C7-cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, Cr-C 6 alkylhalo-O, C 3
-C
6 -alkynyl-O, C 3
-C
6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=O) 2 , Co-C 6 -alkyl-NR 8 , Co-C 6
-NR
8
S(=O)
2 , Co-C 6 -alkyl-S(=0) 2 NR, Co-C6-alkyl-C(=)-NR 8 Co-C 6 -alkyl
NR
8 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C-alkyl C(=O), Co-C 6 -alkyl-NR-C(=O)-O, Co-C6-alkyl-O-C(=O)-NR', Co-C 6 allyl-NR-C(=O)-NR 9 , Co-C 6 -alkyl-NR 8
-C(=NR
9 )NR, Co-C 6 -alkyl
(C=NR
8
)NR
9 , Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O)
NR
8 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 8 ) or Co-C 6 -alkyl-O-N=CR substituents; R', R' and R" 0 are each independently selected from the group consisting of hydrogen, an optionally substituted Cr-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalky-CI-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; B1 represent independently C or N which may further be substituted by G4 groups; G4 groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl,
O-C-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR", 0-C 3
-C
7 -cycloalkyl, O-CI-C 6 -alkyl-heteroaryl, 0-C 1
-C
6 alkylaryl, Co-C 6 -alkyl-OR", C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Cj
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-Cr-C 6 -alkyl, O-heteroaryl, heteroaryl,
CI-C
6 -alkyl-heteroaryl, aryl, O-aryl, Cr-C 6 -alkylaryl, C-C 6 -alkylhalo OR", C 3
-C
6 -alkynyl-OR 11 , C 3
-C
6 -alkenyl-OR", Co-C 6 -alkyl-S-R", 0
C
2
-C
6 -alkyl-S-R' 1 , Co-C 6 -alkyl-S(=O)-R", O-C 2
-C
6 -alkyl-S(=O)-R1, Co-C 6 -alkyl-S(=O) 2 -R", O-C-C 6 -alkyl-S(=O) 2 -R', Co-C 6 -alkyl NR"R 2 , O-C 2
-C
6 -alkyl-NR 1
R'
2 , Co-C 6 -alkyl-S(=O)2NR 11
R
2 , Co-C 6 alkyl-NR'-S(=O) 2
R
2 , O-C 1
-C
6 -alkyl-S(=O) 2 NR R 1 2 , 0-C 2
-C
6 -alkyl NR"1-S(=0) 2 R 2 , Co-C 6 -alkyl-C(=O)-NR"R 1 2 , Co-C 6 -alkyl NR"C(=0)-R", O-CrC6-alkyl-C(=0)-NR1R 1 2 , O-C 2
-C
6 -alkyl
NR"C(=O)-R
2 , Co-C 6 -alkyl-OC(=O)-R", Co-C 6 -alkyl-C(=O)-OR",
O-C
2
-C
6 -alkyl-OC(=O)-R", O-C-C 6 -alkyl-C(=O)-OR 1 , Co-C 6 -alkyl C(=O)-R", 0-C-C 6 -aIlkyl-C(=O)-R' , Co-C 6 -alkyl-NR 1 -C(=O)-OR' , Co-C 6 -alkyl-O-C(=O)-NR"R1 2 or Co-C 6 -alkyl-NR' -C(=0)-NR 2 R1 3 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or WO 2005/123703 PCT/IB2005/002390 33 heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C
C
6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, 0-Cr-C6 alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C 1
-C
6 -alkylaryl, C3-C7 cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C6 alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5;
R'
1 , R" and R1 3 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C3-C7 cycloalkyl-C 1
-C
6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a more preferred aspect of Formula II-A3-a, the compounds of the present invention are represented by Formula II-A3-al below R2 R1 R---N \X--N --- G40 R / N _ R4X N II-A3-al Or a phannaceutically acceptable salt, hydrate or solvate of such compound Wherein R1, R2, R and R 4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C-C 6 -alkyl, Cr1C6 ailyhalo, C 0
-C
6 -alkyl-OR, CO-C 6 -alkyl-NR 5
R
6 , Co-C 6 -alkyl
NR
5
C(=O)-R
6 or CO-C 6 -alkyl-NRS(=O)-R 6 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, 0-Cr-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C3-C6 alkenyl, O-C 3
-C
7 -cycloalkyl, 0-C-C 6 -alkyl-heteroaryl, O-C1-C6 alkylaryl, C-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C6- WO 2005/123703 PCT/IB2005/002390 34 alkyl, O-C 3
-C
7 -cycloalkyl-Ci-C 6 -alkyl, 0-heteroaryl, heteroaiyl, C 1 C 6 -alkyl-heteroaryl, aryl, 0-ary1; Rs and R6 are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C 6 -alkyl, C 1
-C
6 -alkylhalo, C3
C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C1-C6-alkyl, heteroaryl, Ci-C 6 -alkyl heteroaryl, aryl; X is selected from an optionally substituted C 1
-C
6 -alkyl and C1-C6 alkylhalo; G'l groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C6 alkyl, C 1
-C
6 -alkylhalo, O-C 1
-C
6 -alkyl, O-C 1
-C
6 -alkylhalo, 0-C 2
-C
6 alkyl-OR 7 , O-C 3
-C
7 -cycloalkyl, O-Ci-C 6 -alkyl-heteroaryl, 0-C1-C6 alkylaryl, Co-C 6 -alkyl-OR 7 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CI-C6 alkyl, O-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0-heteroaryl, heteroaryl, C1
C
6 -alkyl-heteroaryl, aryl, O-aryl, C 1
-C
6 -alkylaryl, C 1
-C
6 -alkylhalo
OR
7 , Co-C 6 -alkyl-S(=O)-R 7 , O-C 2
-C
6 -alkyl-S(=O)-R 7 , CC-C 6 -alkyl S(=0) 2
-R
7 , O-C 1
-C
6 -alkyl-S(=0) 2
-R
7 , Co-C 6 -alkyl-NR 7
R
8 , O-C 2
-C
6 alkyl-NR 7
R
8 , Co-C 6 -alkyl-S(=O) 2
NR
7 R, Co-C6-alkyl-NR-S(=0)2R',
O-C
1
-C
6 -alkyl-S(=0) 2 NR7R, O-C 2
-C
6 -alkyl-NR 7 -S(=0) 2
R
8 , Co-C 6 alkyl-C(=O)-NR7 R, Co-C 6 -alkyl-NR 7
C(=O)-R
8 , O-C 1
-C
6 -alkyl
C(=O)-NR
7 R', O-C 2
-C
6 -alkyl-NR 7 C(=O)-R', Co-C 6 -alkyl-C(=O)-R 7 ,
O-CI-C
6 -alkyl-C(=O)-R 7 or Co-C 6 -alkyl-NR 7
-C(=O)-NRR
9 substituents; q is an integer from 1 to 4; R, R 8 and R9 are each independently selected from the group consisting of hydrogen, an optionally substituted C 1
-C
6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C 1
-C
6 -alkyl, heteroaryl, C 1
-C
6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a second aspect, the compounds of the present invention are represented by Formula II-A3-al wherein the linker is specified as in the formula II-A3-a2 depicted below WO 2005/123703 PCT/IB2005/002390 35 R2 R' R3 ~NN-G R4N II-A3-a2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R', R2, R 3 and R4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C-C 6 -alkyl, C-C6 alkylhalo, CC-C 6 -alkyl-OR, CO-C 6 -alkyl-NRR 6 , Co-C 6 -alkyl
NR
5 C(=O)-R or Co-C 6 -alkyl-NR 5 S(=0) 2
-R
6 substituents; R5 and R6 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, CI-C 6 -alkylhalo, C 3 C 7 -cycloalkyl, heteroaryl, aryl; C q groups are each independently selected from the group consisting of hydrogen, halogen, nitro, CN, an optionally substituted CrC 6 -alkyl, Cl-C 6 -alkylhalo, O-Co-C 6 -alkyl, O-CO-C 6 -alkylaryl, heteroaryl, aryl or Co-C 6 -alkyl-NR 7
R
8 substituents; q is an integer from 1 to 4; R7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a fourth aspect, the compounds of the present invention are represented by Formula 1-A wherein the heterocyclic ring system is specified as in the formula II A4 depicted below WB w - -- G x f 2 -Gq
B
2 II-A4 WO 2005/123703 PCT/IB2005/002390 36 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R2 R2 R O RN2N R R2 N R R S1 N 0 N N- 0
R
2 N 3 N N N~ N RR R1 R 1 N R ON R N- 0 RR N2 N R 3 N RR N si
R
2 2R 2 R2 R
R
3 R4
R
3 R3 N R1 R23Z R2 N R R 'Y N 4'N R3 NZKZN R2 R1 R2 R1 RA
R
5
R
5 R4 R', R2, R3, R4, R5 and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C 1
-C
6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 2
-C
6 -alkyl-OR6, O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C 1
-C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C1-C 6 alkylaryl, C 1
-C
6 -alkylhalo-OR 6 , C 3
C
6 -akynyl-OR 6 , C 3
-C
6 -alkenyl OR6, Co-C 6 -alkyl-S-R 6 , 0-C 2
-C
6 -alkyl-S-R 6 , Co-C 6 -alkyl-S(=O)-R 6 , 0
C
2
-C
6 -alkyl-S(=O)-R6, C-C6-alkyl-S(=0)2-R6, 0-C 1
-C
6 -alkyl-S(=O) 2 R6, Co-C 6 -alkyl-R 6
R
7 , O-C 2
-C
6 -alkyl-WR 7 , Co-C 6 -alkyl S(=0) 2
NR
6
R
7 , Co-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , 0-C 1
-C
6 -alkyl S(=0) 2 NER , O-Cr-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O)
NR
6
R
7 , Co-C 6 -alkyl-NR 6 C(=0)-R 7 , O-C 1
-C
6 -alkyl-C(=0)-NR 6 R7, O
C
2
-C
6 -alkyl-NR 6 C(=0)-R 7 , Co-C6-alk1-OC(=0)-R6, Co-C6-alkyl
C(=O)-OR
6 , O-C-C 6 -alkyl-OC(=O)-R 6 , O-CC6-alkyl-C(=O)-OR6, Co-C 6 -alkyl-C(=O)-R 6 , O-C-C 6 -alkyl-C(=O)-R6, Co-C,-alkyl-NR C(=0)-OR 7 , Co-C 6 -alkyl-O-C(=0)-NR6R7 or Co-C 6 -alkyl-NR -C(=O)
NR
7 R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with WO 2005/123703 PCT/IB2005/002390 37 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted Cr-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-CI-C 6 -alkyl, O-Cl-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, C-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C 1 C 6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted Cl-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C,-C 6 -alkyl-heteroaryl, aryl; Z, Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted C 1
-C
6 -alkyl, C-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-CI-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, 0-C 3
-C
7 -cycloalkyl, Co-C 6 -alkyl-0,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CO-C 6 -alkyl, S-Co-C 6 -alkyl, C 1
-C
6 alkylhalo-0, C 3
-C
6 -alkynyl-O, C3-C 6 -alkenyl-O, Co-C-alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , CO-C 6
-NR
9
S(=O)
2 , Co-C 6 -alkyl-S(=O) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9
-C(=O)-NR"
0 , Co-C 6 -alkyl-NR 9
-C(=NR'
0 )NR", Co-C 6 -alkyl (C=NR)NR", Co-C 6 -alkyl-C(=0)-O-C-C 6 -alkyl, Co-C 6 -alkyl-C(=O)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents;
R
9 , R1 0 and R" are each independently selected from hydrogen, an optionally substituted C-C 6 -alkyl, Cl-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2 C 6 -alkenyl, C 3
-C
7 -cycloalkyl, C3-C 7 -cycloalky-C-C 6 -alkyl, heteroaryl,
C-C
6 -alkyl-heteroaryl, aryl, heterocycle; B' and B 2 are each independently selected from -C=C-, -C(=O)-, -S(=0) 2 -, -C=N or -C- which may further be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C 6 alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C3-C 6 -alkenyl, O-C 2
-C
6 -alkyl
OR'
2
O-C
3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-Cl-C 6 alkylaryl, Co-C 6 -alkyl-OR 2 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl,
C,-C
6 -alkyl-heteroaryl, aryl, 0-aryl, C-C6-alkylaryl, C,-C 6 -alkylhalo
OR'
2 , C 3
-C
6 -alkynyl-OR", C-C 6 -alkenyl-OR", Co-C 6 -alkyl-S-R 2 , 0- WO 2005/123703 PCT/IB2005/002390 38
C
2
-C
6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R", O-C2-C6-alkyl-S(=0)-RE, Co-C 6 -alkyl-S(=0) 2
-R
12 , O-Cl-C 6 -alkyl-S(=0) 2 -R , Co-C 6 -alkyl
NR'
2 R, O-C 2
-C
6 -alkyl-NRR, Co-C 6 -alkyl-S(=0) 2 N1 2 R', Co-C 6 alkyl-NR 12 -S(=O)2R , O-C-C 6 -alkyl-S(=O) 2 NR&R', 0-CrC 6 -alkyl NR12-S(=0)2R , Co-C 6 -alkyl-C(=O)-NR1 2
R
13 , Co-C 6 -alkyl
NR"
2
C(=O)-R
13 , O-Cr-C 6 -alkyl-C(=O)-NR1 2
R
13 , O-C 2
-C
6 -alkyl
NR
12 C(=O)-R1 3 , Co-C 6 -alkyl-OC(=O)-R 2, Co-C 6 -alkyl-C(=O)-OR 12 ,
O-C
2
-C
6 -alkyl-OC(=O)-R 2 , O-C-C 6 -alkyl-C(=0)-OR' 2 , Co-C 6 -alkyl C(=0)-R 12 , O-Cl-C 6 -alkyl-C&O)-R 12 , Co-C 6 -alkyl-NR1 2 -C(=0)-OR 13 Co-C 6 -alkyl-O-C(=O)-NR R or CO-C 6 -alkyl-NR' 2 -C(0)-NR 3 R 14 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C-C 6 -alkyl, O-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-CrC-alkyl-heteroaryl, O-C1-C6 alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Cj-C 6 -alkyl, O-C3-C7 cycloalkyl-C-C6-alkyl, 0-heteroaryl, heteroaryl, CI-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from I to 5; R , R" and R are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, CrC-6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-CrC6-alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Particularly preferred compounds of the present invention are compounds of Formula II-B w Z1 Gq II-B Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein WO 2005/123703 PCT/IB2005/002390 39 W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R R3-N RA R R1 R R R 3 -NR 2 - R R R , Rs3 N R N N R N N A NA RR
R
3
R
3
R
1
R
1 RN R2N R 2NN ~ N R 2 N__
R
2
R
1
R
2
R
1 R2 R ' R 3 RI R' R3. R2 N R' 4.1 - zI- z9 R N f- N ~ R R 3 NR3 N /I~\A R2 'R R1 R4
R
5 R5R4A
R
1 , R 2 , R, R 4 , R5 and A! m are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alky1, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-CI-C 6 -alkyl, O-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C 3
-C
6 alkenyl, O-C 2
-C
6 -alkyl-OR 6 , O-C3-C 7 -cycloalkyl, 0-CI-C6-alkyl heteroaryl, O-C1-C6-alkylaryl, Co-C 6 -alkyl-OR 6 , C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C 1
-C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0 heteroaryl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C 1
-C
6 alkylaryl, C1-C 6 -alkylhalo-OR 6 , C 3
-C
6 -alkynyl-OR6, C 3
-C
6 -alkenyl OR 6, Co-C 6 -alkyl-S-R 6 , O-C 2
-C
6 -alkyl-S-R 6 , Co-C 6 -alkyl-S(=0)-R 6 , 0
C
2
-C
6 -alkyl-S(=O)-R6, Co-C 6 -alkyl-S(=O) 2 -R6, O-CI-C 6 -alkyl-S(=O) 2 R6, Co-C 6 -alkyl-NRR7, O-C 2
-C
6 -alkyl-NRR 7 , Co-C 6 -alkyl S(=0) 2
NR
6
R
7 , Co-C 6 -alkyl-NR 6
-S(=O)
2
R
7 , O-CI-C6-alkyl S(=0) 2
NR
6
R
7 , O-C 1
-C
6 -alkyl-NR 6 -S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O)
NR
6
R
7 , Co-C 6 -alkyl-NR 6 C(=O)-R7, O-C 1
-C
6 -alkyl-C(=O)-NR 6
R
7 , 0
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , Co-C6-alkyl-OC(=O)-R 6 , Co-C 6 -alkyl
C(=O)-OR
6 , O-C 2
-C
6 -alkyl-OC(=O)-R 6 , O-C 1
-C
6 -alkyl-C(=O)-OR 6 , Co-C 6 -alkyl-C(=O)-R6, O-C1-C 6 -alkyl-C(=O)-R6, -Co-C 6 -alkyl-NR 6 _
C(=O)-OR
7 , Co-C 6 -alkyl-O-C(=O)-NR 6
R
7 or Co-C 6 -alyl-NR 6
-C(=O)
NR
7 R substituents;. wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1
-C
6 -alkyl, C 1
-C
6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C 1
-C
6 -alkyl, O-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalky1, O-CI-C 6 -alkyl-heteroaryl, O-C 1
-C
6
-
WO 2005/123703 PCT/IB2005/002390 40 alkylaryl, CI-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Cj-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-C,-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R 8 are. each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C,-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C6-alkyl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl; Z', Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-CI-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, Co-C 6 -alkyl-O,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-O, C 3
-C
6 -alkynyl-O, C 3
-C
6 -alkenyl-O, Co-C 6 -alkyl-S, CO-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=O) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6
-NR
9 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2
NR
9 , CO-C 6 -alkyl-C(=O)-NR 9 , CO-C-alkyl
NR
9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C6-alkyl NR9-C(=O)-O, Co-C6-alkyl-O-C(=0)-NR9, Co-C 6 alkyl-NR 9
-C(=O)-NR'
0 , Co-C 6 -alkyl-NR 9
-C(=NR'
0 )NR, CC-C 6 -alkyl
(C=NR
9
)NR'
0 , Co-C 6 -alkyl-C(=O)-O-C-C 6 -alkyl, Co-C 6 -alkyl-C(=O)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R', R 1 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalky-Cl-C 6 -alkyl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, heterocycle;
Z
9 , Z1 0 , Z" and Z 1 2 are each independently selected from the group consisting of -C=, -C=C-, -C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 4 Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Ca-C 6 -alkyl, O-Ci-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR1 2
O-C
3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-CI-C 6 alkylaryl, Co-C 6 -alkyl-OR 2 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-CI-C 6 -alkyl, O-heteroaryl, heteroaryl,
C-C
6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR , C 3
-C
6 -alkynyl-OR , C 3
-C
6 -alkenyl-OR 12 , Co-C,-alkyl-S-R", 0
C
2
-C
6 -alkyl-S-R' 2 , Co-C 6 -alkyl-S(=O)-R 2 , O-C 2
-C
6 -alkyl-S(=O)-R' 2 , Co-C 6 -alkyl-S(=0) 2
-R
2 , O-C-C 6 -alkyl-S(=O) 2
-R
2 , Co-C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 41 NR1 2 R1 3 , O-C 2
-C
6 -alkyl-N 1 2 R', Co-C 6 -alkyl-S(=0) 2 NR R", Co-C 6 alkyl-NR 12 -S(0) 2 R", O-C 1
-C
6 -alkyl-S(=0) 2 NR R", O-C 2
-C
6 -alkyl NR 1-S(=0) 2
R
3 , Co-C 6 -alkyl-C(=O)-NR1 R, Co-Cs-alkyl
NR
12 C(=O)-R1 3 , O-Ci-C 6 -alkyl-C(=0)-NRR 12 RD, O-C 2
-C
6 -alkyl
NR
2 C(=O)-R", Co-C 6 -alkyl-OC(=O)-R 2 , Co-C 6 -alkyl-C(=O)-OR 2 ,
O-C
2
-C
6 -alkyl-OC(=O)-R 2 , 0-C 1
-C
6 -alkyl-C(=O)-OR', Co-C 6 -alkyl
C(=O)-R
2 , O-CI-C 6 -alkyl-C(=O)-R 2 , Co-C 6 -alkyl-NR 12 -C(=O)-OR , Co-C 6 -alkyl-O-C(=)-NR R 12 R" or Co-C 6 -alkyl-NR' 2
-C(=O)-NR
3 R1 4 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C 6 -alkyl, C1-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C1-C6-alkyl, O-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-C 1
-C
6 -alkyl-heteroaryl, 0-C1-C6 alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Ci-C 6 -alkyl, O-C 3
-C
7 cycloalkyl-C 1
-C
6 -alkyl, 0-heteroaryl, heteroaryl, C 1
-C
6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from 1 to 4; R1 2 , R" and R1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C 1
-C
6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-Cl-C6-alkyl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl;. Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In one aspect, the compounds of the present invention are represented by Formula II-B wherein the heterocyclic ring system is specified as in the formula II B1 depicted below W
OB
1 HGq N II-Bl Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein WO 2005/123703 PCT/IB2005/002390 42 W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R 2 R 2 O
R
3 -N R x N RI
R
2 ~RR2-N ~ R 1 x R N-~ RR2R2 RR 2R R 3 2R R 3 NR 3 N R
R
2 R1 R R RR A IN/ R 2 N 1 R2 NR N R2N
R
2 R 2
R
1 2RR
R
3 3 3 Z73. R N N R N RNR NT m R2 R R 5 2AR R R, R2, R 3 , R4, R 5 and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C 6 -alkcy1, C 1
-C
6 -alkylhalo, C 2
-C
6 -alkyny1, C 2
-C
6 alkenyl, 0-C1j-C 6 -alkyl, O-C 1
-C
6 -alkcylhialo, O-C3-C 6 -alkyny1, 0-C 3
-C
6 alkenyl, 0-C 2
-C
6 -alkyl-OR 6 , 0-C 3
-C
7 -cycloalkyl, 0-C1-C 6 -alkyl heteroaryl, 0-C1-C 6 -alkylary1, Co-C-alkyl-ORG, C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C 1
-C
6 -alkyl, 0-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0 heteroaryl, heteroary1, C1-Cs-alkyl-heteroaryl, aryl, 0-aryl, C 1
-C
6 alkylaryl, C1-C 6 -alkylhalo-OR 6 , C 3 -. C 6 -alkynyl-OR6, C 3
-C
6 -alkenyl OR, Co-C6-alkyl.-S-R, O-C 2
-C
6 -alkyl-S-R, Co-C 6 -alkyl-S(=0)-R, 0
C
2
-C
6 -alkyl-S(=O)-R, Co-C 6 -alkyl-S(=o) 2 -R, 0-Ci-C 6 -alkyl-S(=O) 2 R, Co-C 6 -alkylNRhRR, 0-C 2
-C
6 -alkyl-NR 6
R
7 , Co-C3-alkyl S(=0) 2
NR
6
R
7 , Co-C 6 -alkyl-NR 6 -S(=o) 2
R
7 , 0-CI-C 6 -alkyl S(=0) 2
NR
6
R
7 , O-C-C 6 -alkyl-NR 6
-S(=O)
2
R
7 , Co-C 6 -alkyl-C=)
NRR
7 Y, Co-C 6 -alkyl-NR 6 C(=0)-R 7 , O-C 1
-C
6 -alkyl-C(=0)-NR 6 R, 0
C
2
-C
6 -alkyl-NR 6 C(=o)-R 7 , Co-C 6 -alkyOC()-R 6 , Co-C-alkyl
C(=O)-OR
6 , O-C 2
-C
6 -alkyl-OC(=0)-R 6 , 0-Ci-C 6 -alkyl-C(=O)-R 6 , Co-C6-alkyl-C(=O)-R 6 , O-C 1
-C
6 -alkyl-C(=0)-R 6 , Co-C 6 -alkyl-NR 6 C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=0)-NR 6
R
7 or Co-C 6 -alkCyl-N 6 -C(=0)
NR
7
R
8 sub stituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted Ci-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkyny1, C 2
-C
6 alkenyl, 0-C 1
-C
6 -alky, O-C 1
-C
6 -alkylhalo, O- 3
-C
6 -alkynyl, 0-C 3
-C
6 alkenyl, 0-C 3
-C
7 -cycloalky1, O-C 1
-C
6 -alkyl-heteroaryl, o-Ci-C 6
-
WO 2005/123703 PCT/IB2005/002390 43 alkylaryl, C-C 6 -alkylaryl, C-C 7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-CI-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl;
R
6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-Cl-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 Am groups; m is an integer from 1 to 5; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3 -C-cycloalkyl, Co-C 6 -alkyl-O,
C
3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Co-C6-alkyl,
S-CO-C
6 -alkyl, CrC-6 alkylhalo-O, C 3
-C
6 -alkynyl-O, C 3
-C
6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0)2, C 0
-C
6 -alkyl-NR 9 , CO-C 6 -NRS(=0) 2 , CO-C-alkyl-S(=O) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=0), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=0)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR-C(=0)-NRI', Co-C 6 -alkyl-NR-C(=NR' 0 )NR", Co-C 6 -alkyl
(C=NR
9
)NR"
0 , Co-C 6 -alkyl-C(=O)-O-Co-C6-alkYl, Co-C 6 -alkyl-C(=O) NR-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR?) or C 0
-C
6 -alkyl-O-N=CR 9 substituents; R', R' 0 and R" are each independently selected from hydrogen, an optionally substituted C-C 6 -alkyl, C,-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2 C 6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalky-C-C6-alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, heterocycle; Bi represents independently C or N which may father be substituted by Gq groups; G4 groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl,
O-C-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR1 2 , O-C 3
-C
7 -cycloalkyl, 0-Cl-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Co-C-alkyl-OR 2 , C 3
-C
7 -rcycloalkyl, C 3 -Crcycloalkyl-C
C
6 -alkyl, O-Cj-C 7 -cycloalkyl-C-C6-alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, O-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR1 2 , C 3
-C
6 -alkynyl-OR 2 , C 3
-C
6 -alkenyl-OR 12, C 0
-C
6 -alkyl-S-R , O
C
2
-C
6 -alkyl-S-R 1, Co-C 6 -alkyl-S(=O)-R 2 , O-C 2 -C6-alkyl-S(=O)-R, Co-C 6 -alkyl-S(=0) 2
-R
2 , O-C-C 6 -alkyl-S(=O) 2 -R1 2 , CO-C 6 -alkyl
NR'
2 R", O-C 2
-C
6 -alkyl-NR 1 2
R
3 , Co-C 6 -alkyl-S(=0) 2 NR R , Co-C6 alkyl-NR -S(=0) 2 R", O-Cr-C 6 -alkyl-S(=O) 2 NR 2
R
3 , O-C 2
-C
6 -alkyl- WO 2005/123703 PCT/IB2005/002390 44
NR
12
-S(=O)
2 R", Co-C 6 -alkyl-C(=O)-NRR 12 R', Co-C 6 -alkyl
NR'
2 C(=O)-R", O-C-C 6 -alkyl-C(=0)-NR R , O-C 2
-C
6 -alkyl
NR
12 C(=O)-R, Co-C 6 -alkyl-OC(=O)-R 2 , Co-C 6 -alkyl-C(=O)-OR 2 ,
O-C
2
-C
6 -alkyl-OC(=O)-R 2 , O-Cr-C 6 -alkyl-C(=O)-OR1 2 , Co-C 6 -alkyl C(=O)-R , O-C 1
-C
6 -alkyl-C(=O)-R 2 , Co-C 6 -alkyl-NRI)-C(=O)-OR", Co-C 6 -alkyl-O-C(=O)-NR1 R3 or CO-C 6 -alkyl-NR 2 -C(=O)-NR1 3
R
4 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C 1 C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-C 1
-C
6 alkyl, O-CI-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 cycloalkyl, O-Cl-C 6 -alkyl-heteroaryl, O-CI-C 6 -alkylaryl, C 3
-C
7 cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, O-aryl; q is an integer from 1 to 2; R , R" and R14 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a second aspect, the compounds of the present invention are represented by Formula II-B wherein the heterocyclic ring system is specified as in the formula II B2 depicted below W NB1 N Gq II-B2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered WO 2005/123703 PCT/IB2005/002390 45 ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R2 R 2 O Ri RRRR 3 -NN R RR
R
1 R' N-~ R2 ~~ N 3< 'N R2N RN N
R
2
R
2
R
2
R
1 R ' R 2 R 3 R 4 R N">+ />N N R 1 R2 R NN' R2N R~ N N 3 N
R
2
R
1
R
2 R' R- 3 NR R 3 N 1R1 R R 2 N R3 N N N N 3NR NIr R3 R 5 R4
R
1 , R2, R, Ri, Ri and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Cr-C 6 -alkyl, Cr-C 6 -alkylhalo, CrC 6 -alkynyl, Cr-C 6 alkenyl, 0-Cr-C6-alkyl, 0-Cr-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, 0-C 3
-C
6 alkenyl, 0-Cr-C 6 -alkyl-OR, O.-CrC 7 -cycloalkyl, O-Ci-C 6 -alkyl heteroaryl, O-Cr-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , Cr-C 7 -cycloalkcyl, Cr Cr-cycloalkyl-Cr-C 6 -alkyl, O-Cr-C 7 -cycloalkyl-Cr-C 6 -alkyl, 0 heteroaryl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, 0-aryl, Cr-C 6 alkylaryl, Cr-C 6 -alkylhalo-OR 6 , Cr-C 6 -alkynyl-OR 6 , Cr-C 6 -alkenyl OR , Co-C 6 -alkyl-S-R6, O-Cr-C 6 -alkyl-S-R6, Co-C 6 -alkyl-S(=O)-R6 , 0
C
2
-C
6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=0)r~R 6 , 0-r6aklS=) Ri, Co-C 6 -alkyl-NR 6
R
7 , O-Cr-C 6 -alkyl-NR 6
R
7 , Co-C6-alkcyl S(=0) 2 NR6R7, Co-C 6 -alkyl-NR 6
-S(=)
2
R
7 , 0-Ci-C 6 -alkyl S(=0) 2
NR
6
R
7 , O-Cr-C 6 -alkyl-N"R 6 -S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O0)
NR
6
R
7 , Co-C 6 -alkyl-NR 6 C(=0)-R 7 , O-Cr-C 6 -alkcyl-C(=0)-NR 6
R
7 , 0 6 7 6
CRC
6 -alkyl-NR C(=0)-R, Co-C 6 -alkyl-OC(=0)-R , Co-C-alkyl C(=0)-OR , O -Cr6-alkyl-C(-R , O-C-C 6 -alkyl-C(=0)-OR 6 Co-C 6 -alkyl-C(=0)-R6, O-C-C 6 -alkyl-C(=O)-R 6 , -alkyl-6_ C(=0)-Ry, Co-C 6 -alkyl-O-C(=O)-NR 6
R
7 or Co-C 6 -alkyl-NR 6 -C(=0)
NR
7
R
8 sub stituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C6-alkyl, CrC- 6 -alkylhalo, CC 6 -alkynyl, Cr.C 6 alkenyl, O-CrC 6 -alky, O-C-C 6 -alkylhalo, O-CrC 6 -alkynyl, 0-Cr-C 6 alkenyl, 0-CrC 7 -cycloalkyl, O-C 1
-C
6 -alkyl-heteroaryl, 0-Cr-C 6 alkylaryl, CrC 6 -alkylaryl, CrCrcycloalkyl, Cr-C-cycloalkyl-CrC 6
-
WO 2005/123703 PCT/IB2005/002390 46 alkyl, O-C 3
-C
7 -cycloalky1-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl;
R
6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C6-alkyl, C-C6 alkylhalo, C2-C6-alkynyl, C 2 -C6-alkenyl, C3-C7-cycloalkyl, C3-C7 cycloalkyl-C-C 6 -alkyl, heteroaryl, CrC6-alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C2-C6-alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0
C
3 -C6-alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, Co-C6-alkyl-O,
C
3
-C
7 -cycloalkyl, C3-C7-cycloalkyl-Co-C 6 -alkyl, S-Co-C6-alkyl, Cr-C 6 alkylhalo-O, C3-C6-alkynyl-0, C 3 -C6-alkenyl-0, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=0), Co-C 6 -alkyl-S(=O) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6
-NR
9 S(=0) 2 , Co-C6-alkyl-S(=0) 2
NR
9 , Co-C 6 -alkyl-C(=0)-NR 9 , Co-C 6 -alkyl
NR
9 C(=O), Co-C6-alkyl-OC(=O), Co-C 6 -aIkyl-C(=O)-O, Co-C6-alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR', Co-C 6 -allcYl-NR 9 -C(=NR1 0 )NR", Co-C 6 -alkyl
(C=NR
9
)NR
0 , Co-C6-alkyl-C(=O)-O-Co-C6-alkyl, Co-C 6 -alkyl-C(=O)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents;
R
9 , R' 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C1-C6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C3-C 7 -cycloalkyl, C 3
-C
7 cycloalky-C-C 6 -alkyl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, heterocycle; B1 represents independently C or N which may further be substituted by one Gq group; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, CI-C6-alkylhalo, C2-C 6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl, O-Cl-C 6 -alkylhalo, 0-C 3
-C
6 -alkynyL, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl
OR'
2 0-C 3
-C
7 -cycloalkyl, O-C-C6-alkyl-heteroaryl, 0-C1-C 6 alkylaryl, Co-C 6 -alkyl-OR 2 , C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C
C
6 -alkyl, O-C3-C 7 -cycloalkyl-CI-C 6 -alkyl, 0-heteroaryl, -heteroaryl, Cr-C6-alkyl-heteroaryl, aryl, 0-aryl, CI-C 6 -alkylaryl, C-C 6 -alkylhalo OR1 2 , C 3
-C
6 -alkynyl-OR 2 , C 3
-C
6 -alkenyl-OR 12 , Co-C 6 -alkyl-S-R 12 , O
C
2
-C
6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R 2 , O-C 2
-C
6 -alkyl-S(=O)-R, Co-C 6 -alkyl-S(=0) 2 -R, 0-C-C 6 -alkyl-S(=0) 2 -R1, Co-C 6 -alkyl
NR'
2 R1', 0-C 2
-C
6 -alkyl-NR 2 R1 3 , Co-C 6 -alkyl-S(=0) 2 NRR"', Co-C6 alkyl-NR 2 -S(=0) 2
R
3 , O-C-C 6 -alkyl-S(=0) 2 NR1 2
R
3 , 0-C2-C6-alkyl- WO 2005/123703 PCT/IB2005/002390 47 NR'-S(=0) 2
R'
3 , Co-C 6 -alkyl-C(=0)-NR R , Co-C 6 -alkyl
NR
12 C(=O)-R, O-Cl-C 6 -alkyl-C(=0)NR 2
R
1 3 , O-C 2
-C
6 -alkyl
NR
2 C(=O)-R, Co-C6-alkyl-OC(=O)-R 2, Co-C6-a1kyl-C(=O)-OR 2 ,
O-C
2
-C
6 -alkyl-OC(=O)-R 2 , O-C-C 6 -alkyl-C(=O)-OR 12 , Co-Cs-alkyl
C(=O)-R
12 , O-CI-C 6 -alkyl-C(=O)-R 12 , Co-C6-a&lklR12-C(=0)-OR3, Co-C 6 -alkyl-O-C(=O)-NR 2 R" or Co-C 6 -alkyl-NR' 2 -C(=O)-NR1 3 R14 substituents; wherein optionally two substituents are combined to the intervening atoms to forn a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C
C
6 -alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, 0-CI-C 6 alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-Cl-C 6 -alkylaryl, C 3
-C
7 cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 alkyl, 0-heteroaryl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, 0-aryl; q is an integer from 1 to 3; R1 2 , R" and R 1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Further preferred compounds of the present invention are compounds of Formula II-C
~--B=-B
2 x
B
3 Gq II-C Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: WO 2005/123703 PCT/IB2005/002390 48 S: N Nj 0 R2 R2 R R< R2 N R 3 N R N N sR R2 RN RR R 2R 2 N R N N 7 R2 R2 R2 R' R3 R R R3 R 1
R
2 N R 2 N R 1 R NNR3 N~ R 3
R
3 N-T
R
2
R
1
R
2
R
1 R
R
3
"NR
3
R
2 0Z2 Z'3Z 2 R4 R 4 ' N-N' R3 N N 7<zN1e
R
5
R
5
R
4
A
1 R1, R 2 , R, R 4 , R 5 and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C 1
-C
6 -alkyl, O-Ci-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 2
-C
6 -alkyl-OR 6 , O-C 3
-C
7 -cycloalkyl, O-Ci-C 6 -alkyl 6 heteroaryl, O-Ci-C 6 -alkylaryl, Co-C 6 -alkyl-OR , C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C 1
-C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0 heteroaryl, heteroaryl, Cl-C6-alkyl-heteroaryl, aryl, O-aryl, C 1
-C
6 alkylaryl, C 1
-C
6 -alkylhalo-OR 6 , C 3
-C
6 -alkynyl-OR 6 , C 3
-C
6 -alkenyl OR6, Co-C 6 -alkyl-S-R 6, O-C2-C 6 -alkyl-S-R6, Co-C 6 -alkyl-S(=O)-R6, 0_
C
2
-C
6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=0) 2
-R
6 , O-Ci-C 6 -alkyl-S(=O) 2 R6, Co-C6-alkylNR67, O-C 2
-C
6 -alkyl-NR 6
R
7 , Co-C 6 -alkyl S(=0) 2
NR
6
R
7 , Co-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , O-CI-C 6 -alkyl S(=0) 2
NR
6
R
7 , 0-C1-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , Co-C 6 -alkyl-C(=O)
NR
6
R
7 , Co-C 6 -alkyl-NR 6
C(=O)-R
7 , O-Ci-C 6 -alkyl-C(=O)-NR 6
R
7 , 0
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl
C(=O)-OR
6 , O-C 2
-C
6 -alkyl-OC(=O)-R 6 , O-C 1
-C
6 -alkyl-C(=O)-OR , Co-C 6 -alkyl-C(=O)-R 6 , O-C1-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 C(=O)-OR, Co-C 6 -alkyl-O-C(=O)-NR 6
R
7 or Co-C 6 -alkyl-NR 6
-C(=O)
NR
7
R
8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C 1
-C
6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-Ci-C 6 -alkyl, O-C1-C 6 -alkylhalo, O-C 3 -C6-alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-CI-C6-alkyl-heteroaryl,
O-C
1
-C
6 alkylaryl, Cl-C6-alkylaryl, C3-C 7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C 1
-C
6 alkyl, O-C 3
-C
7 -cycloalkyl-C 1
-C
6 -alkyl, 0-heteroaryl, heteroaryl, C 1 C6-alkyl-heteroaryl, aryl, O-aryl;
R
6 , R7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C-alkyl, C 1
-C
6
-
WO 2005/123703 PCT/IB2005/002390 49 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-Cr-C 6 -alkyl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl; ZI, Z2, Z3, Z4, ZI, Z6, Z7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A"' groups; m is an integer from I to 5; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C2-C 6 -alkynyl, C 2
-C
6 -alkenyl, O-Co-C 6 -alkyl, O-Cr-C 6 -alkylhalo, 0
C
3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 -cycloalkyl, Co-C 6 -alkyl-O,
C
3
-C
7 -cycloalkyl, C3-C 7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-O, C 3
-C
6 -alkynyl-O, C 3
-C
6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6
-NR
9 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl
NR
9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR?-C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR-C(=O)-NR 10 , Co-C 6 -alkyl-NR 9
-C(=NR
0 )NR", Co-C 6 -alkyl
(C=NR
9 )NR , Co-C6-alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O)
NR
9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents;
R
9 , R' 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle;
B
1 , B 2 and B 3 are each independently selected from C or N which may further be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Cl-C 6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR, O-C-C 7 -cycloalkyl, O-Ci-C6-alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR , C 3
-C
7 -cycloalkyl, C3-C7-cycloalkyl-C
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cl-C6-alkyl-heteroaryl, aryl, 0-aryl, Cl-C 6 -alkylaryl, C-C 6 -alkylhalo 12 12 12 12 OR , C-C 6 -alkynyl-OR , C 3
-C
6 -alkenyl-OR , Co-C 6 -alkyl-S-R , 0
C
2
-C
6 -alkyl-S-R , Co-C 6 -alkyl-S(=0)-R, 0-C 2 -C6-alkyl-S(=O)-R, Co-C 6 -alkyl-S(=)R 12 , -C-C 6 -alkyl-S(=0) 2
-R
2 , Co-C 6 -alkyl NR2R1, O-C 2
-C
6 -alkyl-NR 12
R
3 , Co-C 6 -alkyl-S(=O) 2 NR R" , Co-C 6 alkyl-NR 2 -S(=0) 2 R1 3 , O-C-C 6 -alkyl-S(=0) 2
NR
2
R
1 3 , O-C 2
-C
6 -alkyl NR-S(=0)2RI Co-C 6 -alkyl-C(=O)-NR 2 R 13 , Co-C 6 -alkyl
NR
2
C(=O)-R
3 , O-C-C 6 -alkyl-C(=0)-NR1 2 Ri 3 , O-C 2
-C
6 -alkyl
NR
12 C(=O)-R", Co-C 6 -alkyl-OC(=O)-R 12 , Co-C 6 -alkyl-C(=O)-OR 2 ,
O-C
2
-C
6 -alkyl-OC(=O)-R 12 , O-CI-C6-alkyl-C(=O)-OR , Co-C 6 -alkyl C(=O)-R , O-C-C 6 -alkyl-C(=0)-R 2 , Co-C 6 -alkyl-NR' 2
-C(=O)-OR
3
,
WO 2005/123703 PCT/IB2005/002390 50 Co-C-alkyl-O-C(=0)-NR RI or Co-C 6 -alkyNR12C(=O)-NR R14 substituents; wherein optionally two substituents are combined to the intervening atoris to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C 1 C 6 -alkyl, C1-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, 0-C1-C 6 alkyl, O-C1-C-alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 3
-C
7 cycloalkyl, O-C1-C 6 -alkyl-heteroaryl, O-C1-C-alkylaryl,
C
3
-C
7 cycloalkyl, C3-C 7 -cycloalkyl-C-C 6 -alky, O-C 3
-C
7 -cycloalkyl-C-C 6 alkyl, 0-heteroaryl, heteroaryl, C1-Cs-alkyl-heteroaryl, aryl, 0-aryl; q is an integer from I to 5; R1 2 , R" and R1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C 6 -alkyl, C 1
-C
6 alkylhalo, C2-C 6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3 -C7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C6-alkyl-heteroaryl, aryl; Any N may be an N-oxide; provided that: when X is independently selected from NR'5, 0, S or an optionally substituted C-C 6 -alkyl, Gq and q are as defined above, W is an optionally substituted 2-pyridinyl and R 15 is independently selected from hydrogen, an optionally substituted CI-C 6 -alkyl, Cr-C 6 -alkylhalo,
C
2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Cl
C
6 -alkyl, heteroaryl, C-C6-alkyl-heteroaryl or aryl, B 1 , B 2 and B 3 can not be C; when X is 0, B1, B 2 and B 3 are each independently selected from C or N, Gq and q are as defined above, W can not be an optionally substituted 3-pyridazinyl or 4-pyrimidinyl; when X is CH 2 , B', B 2 and B 3 are C and Gq and q are as defined above, W can not be 2-phenyloxazol-4-yl, 4-phenyloxazol-2-yl, 4-(3 (benzyloxy)propyl)-oxazol-2-yl, 4-phenylthiazol-2-yl, 4-methylthiazol 2-yl, benzo[d]oxazol-2-yl or benzo[d]thiazol-2-yl; when X is 0, W-is an optionally substituted pyridinyl and Gq and q are as defined above, B', B 2 or B 3 can not be N; when X is CH 2
CH
2 , B1, B 2 and B 3 are C and G" and q are as defined above, W can not be 4-imidazolyl. The present invention includes both possible stercoisomers and includes not only racemic compounds but the individual enantiomers as well.
WO 2005/123703 PCT/IB2005/002390 51 In a more preferred aspect of formula II-C Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R- R I R R
S
1
R
1 R1R R R2 R2 R R 3 R 3 R N N RI R 1
R
2
R
1 RI 3 + I>-+Z RT2Z -. Z_ R2 N R2" N ~ N N R 1 R R
A"
m R, R 2
R
3 , R 4 , R and A m are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C 6 -alkcyl, C1-C 6 -alkylhalo, C2-C6-alkcynyl,
C
2
-C
6 alkenyl, 0-CrRC 6 -alkyl, O-CC 6 -alkylhalo, O-C3-C 6 -alkynyl, 0-C 3
-C
6 alkenyl, 0-C 2
-C
6 -alkyl-OR 6 , 0-C 3
-C
7 -cycloalkyl, 0-Cr-C 6 -alkyl heteroaryl, O-C1-C6-alkylaryl, Co-C 6 -alkyl-OR 6 , C 3
-C
7 -cycloalkyl, C 3 C7-cycloalkyl-C 1
-C
6 -alkyl, 0-C3-C7-cycloalkcyl-C1-C 6 -alkyl, 0 heteroaryl, heteroaryl, Cr-C6-alkyl-heteroaryl, aryl, O-aryl, Cr-C 6 alkylaryl, C1-C 6 -alkylhalo-OR 6 , C 3
-C
6 -alkynyl-OR 6 , C 3
-C
6 -alkenyl-. 6 6 OR, Co-C 6 -alkyl-S-R 6 , o-C 2
-C
6 -alkyl-S-R 6 , Co-C 6 -alkyl-S(=0)-R, o C -C 6 -alkcyl-S(=0)-R, Co-C 6 -alkyl-S(=O) 2
-R
6 , O-CrC 6 -alkyl-S(=0) 2 R , Co-C-alkyl-NR R, O-C2-C 6 - alky-NR 6
R
7 , Co-C 6 -alkyl
S(=O)
2
NR
6
R
7 , Co-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , O-CI-C 6 -alkyl S(=0) 2
NR
6
R
7 , O-C rC 6 -alkyl-NR 6
-S(=O)
2
R
7 , Co-C 6 -alkyl-C(=0) NR RY, Co-C 6 -alkyl-NR6C(=0)-R, 0-C-C6-alkyl-C(=O)-NR 6 Ry, 0
C
2
-C
6 -a -NR 6
C(=O)-R
7 , Co-C 6 -alkyOC(=O)-R 6 , Co-C-alkyl C(=0)-OR 6 , O-C 2 -C6-alkyl-OC(=0)-R,
-C-C
6 -alkyl-C(=O)-OR 6 , Co-C6-alkyl-C(=O)-R 6 , O-CrC6-alkyl-C(=0)-R 6 , Co-C 6 -alkyl-NR 6 C(=O)-OR 7 , Co-C6-akyl--C(=)-NR 6
R
7 or Co-C6-alkyl-N 6 -C(=0)
NR
7
R
8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with WO 2005/123703 PCT/IB2005/002390 52 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, Ci-C 6 -alkylhalo, C2-C6-alkynyl, C2-C6 alkenyl, O-CI-C 6 -alkyl, O-C-C 6 -alkylhalo, 0-C3-C6-alkynyl, 0-C3-C6 alkenyl, O-C 3
-C
7 -cycloalkyl, O-Cl-C6-alkyl-heteroaryl, 0-C-C6 alkylaryl, Cl-C6-alkylaryl, C 3
-C
7 -cycloalkyl, C3-C7-cycloalkyl-C 1
-C
6 alkyl, O-C 3
-C
7 -cycloalkyl-Cr-C 6 -alkyl, 0-heteroaryl, heteroaryl, Ci
C
6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R 7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted C1C6-alkyl, C1-C6 alkylhalo, C 2
-C
6 -alkyny1, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-Cr-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; ZI, Z2, Z3, Z 4 , ZI, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted C 2
-C
6 -alkynyl, Co-C 6 -alkyl
NRS(=O
2 , Co-C 6 -alkyl-S(=O) 2
NR
9 , Co-C 6 -alkyl-C(=O)-NR 9 , CO-C 6 alkyl-NR C(=O), Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl
C(=O)-NR
9
-CO-C
6 -alkyl, Co-C 6 -alkyl-OC(=O) or Co-C 6 -alkyl-C(=O)-O substituents; R9 is selected from hydrogen, an optionally substituted CI-C 6 -alkyl, C
C
6 -alkylhalo, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl;
B
1 , B 2 and B3 are each independently selected from C or N which may further be substituted by Gq groups; Gq groups are each independently selected from .the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1C6 alkyl, CI-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, O-Ci-C 6 -alkyl,
O-C-C
6 -alkylhalo, O-C3-C6-alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl
OR'
0 , O-C 3
-C
7 -cycloalkyl, O-C-6-alkyl-heteroaryl, 0-CrC6 alkylaryl, Co-C 6 -alkyl-OR' 0 , C3-C 7 -cycloalkyl, C3-C 7 -cycloalkyl-Cl
C
6 -alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl,
C.-C
6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo
OR
0 , C 3
-C
6 -allynyl-OR 10 , C 3
-C
6 -alkenyl-OR 0 , Co-C 6 -alkyl-S-R 0 , 0
C
2
-C
6 -alkyl-S-R, Co-C 6 -alkyl-S(=O)-R' 0 , O-C 2
-C
6 -alkyl-S(=O)-R1 0 , Co-C 6 -alkyl-S(=O) 2
-R'
0 , O-C-C 6 -alkyl-S(=O) 2 -R1 0 , Co-C6-alkyl
NR'
0 R", O-C 2
-C
6 -alkyl-NR 0
R
11 , Co-C 6 -alkyl-S(=0) 2
NR'
0 R', Co-C6 alkyl-NR' 0
-S(=O)
2 R", O-C-C 6 -alkyl-S(=O) 2
NR'
0 R"1, O-C2-C 6 -alkyl NRI0-S(=0)2R1, Co-C 6 -alkyl-C(=O)-NR' 0 R", Co-C6-alkyl
NR'
0 C(=O)-R", O-CI-C 6 -alkyl-C(=O)-NR' 0 Ru, O-C 2
-C
6 -al1Yl NR1 0 C(=O)-R", Co-C 6 -alkyl-OC(=O)-R" 0 , Co-C6-alkyl-C(=0)-OR10,
O-C
2
-C
6 -alkyl-OC(=0)-R1 0 , O-CI-C 6 -alkyl-C(=O)-OR0, Co-C,-alkyl
C(=O)-R"
0 , O-C-C 6 -alkyl-C(=O)-R' 0 , Co-C 6 -alkyl-NR -C(=O)-OR", WO 2005/123703 PCT/IB2005/002390 53 Co-C 6 -alkyl-O-C(==O)-N 10 R" or Co-C 6 -alkyl-NR' 0 -C(=O)-NR"R 12 substituents; q is an integer from 1 to 5;
R
0 , R" and R1 2 are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C 6 -alkyl, C 1
-C
6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C6-alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. In a second more preferred aspect of formula II-C Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fased with a 5- or 6- membered ring containing one or more atoms independently selected from a group consisting of C, N, 0 and S; provided that W can not be a pyridine and W is a heteroaryl selected from the group of formula:
R
2
R
2
R
1
R
2 R3-N RR23< R RN RI R2~ R1<\ R 0 R N R R2NN R R ON
R
2 N R 3 N R 2 N N N/ R2 R2 R1 R - R 3 N3 N R R 2 N R 2 NN RI R1-<j3
R
3
NR
3 1 N!
R
2
R
1
R
2
R
1 R1
N
3
R
3
R
2 0 Z322 ZrZ Z3,Z2 -~ -
-
Z R4N N4 N- 3 N R5 R5 R4 Am R1, R 2 , R 3 , R 4 , Rs and A"I are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1
-C
6 -alkyl, Ci-C 6 -alkylhalo, 'C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-C 1
-C
6 -alCyl, O-C 1
-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6
-
WO 2005/123703 PCT/IB2005/002390 54 alkenyl, O-C 2
-C
6 -alkyl-OR 6 , 0-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR6, C 3
-C
7 -cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, 0-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0 heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, 0-aryl, CI-C 6 alkylaryl, CI-C 6 -alkylhalo-0R 6 , C 3
-C
6 -alkynyl-OR6, C 3
-C
6 -alkenyl
OR
6 , Co-C 6 -alkyl-S-R 6 , O-C 2
-C
6 -alkyl-S-R, C 0 -C6-alkyl-S(=0)-R 6 , 0
C
2
-C
6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=0) 2
-R
6 , 0-C-C 6 -alkyl-S(=O) 2 R6, Co-C 6 -alkylNR6R7, 0-C 2
-C
6 -alkylNR 6
R
7 , Co-C 6 -alkyl S(=0) 2
NR
6
R
7 , Co-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , 0-C-C 6 -alkyl S(=0) 2
NRR
7 , 0-CI-C 6 -alkyl-NR 6 -S(=0) 2
R
7 , CC-C 6 -alkyl-C(=O)
NR
6
R
7 , Co-C,-alkyl-NR 6
C(=O)-R
7 , 0-C 1
-C
6 -alkyl-C(=0)-NR 6
R
7 , 0
C
2
-C
6 -alkyl-NR 6
C(=O)-R
7 , Co-C 6 -alkyl-OC(=0)-R6, Co-C 6 -alkyl
C(=O)-OR
6 , O-C 2
-C
6 -alkyl-OC(=O)-R 6 , 0-C-C 6 -alkyl-C(=0)-0R 6 , Co-C 6 -alkyl-C(=0)-R 6 , O-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 C(=0)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR 6
R
7 or Co-C6-alkyl-N -C(=O)
NR
7
R
8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 alkenyl, O-Ci-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 alkenyl, O-C 3
-C
7 -cycloalkyl, 0-C-C 6 -alkyl-heteroaryl, 0-CI-C 6 alkylaryl, C-C 6 -alkylaryl, C 3
-C
7 -cycloalkyl, C 3
-C
7 -cycloalkyl-CI-C 6 alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C
C
6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted CrC 6 -alkyl, C-C 6 alkyihalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-CrC 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Z1, Z2, Z3, Z4, Z , Z6, Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from I to 5; X is selected from an optionally substituted CI-C 6 -alkyl, C 2
-C
6 -alkynyl,
O-CO-C
6 -alkyl, CO-C 6 -alkyl-O, 0-C 3
-C
6 -alkynyl, S-Co-C-alkyl, Co-C 6 alkyl-S, Co-C 6 -alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , S(=O) 2 -Co-C-alkyl-, Co-C 6 -alCyl-NR, NlR-Co-C 6 -alkyl, Co-C 6
-NR
9 S(=0) 2 , Co-C 6 -alkyl S(=0) 2
NR
9 , Co-C 6 -alkyl-C(=0)-NR 9 , Co-C 6 -alkyl-NR 9 C(=O), Co-C 6 alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O)-NR 9 -Co-C 6 -alkyl, C(=O)-Co-C 6 -alkyl or Co-C 6 -alkyl-C(=0) substituents;
R
9 is selected from hydrogen, an optionally substituted Ci-C 6 -alkyl, Ci
C
6 -alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalky-C-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; WO 2005/123703 PCT/IB2005/002390 55
B
1 , B2 and 3 are each independently selected from C or N which may further be substituted by GI groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1
-C
6 alkyl, C-C 6 -alkylhalo, C2-C 6 -alkynyl, C 2
-C
6 -alkenyl, O-C-C 6 -alkyl,
O-C-C
6 -alkylhalo, O-C 3
-C
6 -alkynyl, O-C 3
-C
6 -alkenyl, O-C 2
-C
6 -alkyl OR", O-C 3
-C
7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl,
O-CI-C
6 alkylaryl, Co-C 6 -alkyl-OR" 0 , C3-C 7 -cycloalkyl, C 3
-C
7 -cycloalkyl-Cj C6-alkyl, O-C 3
-C
7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl,
C-C
6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR'), C 3
-C
6 -allynyl-OR1 0 , C 3
-C
6 -alkenyl-OR 0 , Co-C 6 -alkyl-S-R' 0 , 0
C
2
-C
6 -alkyl-S-R' 0 , Co-C 6 -alCyl-S(=0)-R1' 0 , O-C 2
-C
6 -alkyl-S(=O)-RD, Co-C 6 -alkyl-S(=0) 2
-R'
0 , O-CI-C6-alkyl-S(=0) 2 -R1 0 , Co-C 6 -alkyl
NR'
0 R", O-C 2
-C
6 -allC-NR' 0 R", Co-C 6 -akyl-S(=0) 2
NR"
0 R", Co-C 6 alkyl-NR' 0 -S(=0) 2 R', O-C-C 6 -alkyl-S(=0) 2
NR
0 R", O-C 2
-C
6 -alkyl NR1-S(=0)2R Co-C 6 -alkyl-C(=O)-NR' 0 R", Co-C 6 -alkyl
NR'
0 C(=O)-R", O-C-C 6 -alkyl-C(=O)-NR1 0 R", O-C 2
-C
6 -alkyl
NR'
0 C(=O)-R", Co-C 6 -alkyl-OC(=O)-R1 0 , Co-C6-alkyl-C(=O)-OR",
O-C
2
-C
6 -alkyl-OC(=O)-RD, O-C-C 6 -alkyl-C(=O)-OR 0 , Co-C 6 -alkyl C(=O)-R, O-C-C 6 -alkyl-C(=O)-R' 0 , Co-C 6 -alkyl-NR'-C(=O)-OR", Co-C 6 -alkyl-O-C(=O)-NR'"R' or Co-C 6 -alkyl-NR' 0 -C(=O)-NR"R2 substituents; q is an integer from 1 to 5;
R'
0 , R" and R1 2 are each independently selected from the group consisting of hydrogen, an optionally substituted C,-C 6 -allcyl, CI-C 6 alkylhalo, C 2
-C
6 -alkynyl, C 2
-C
6 -alkenyl, C 3
-C
7 -cycloalkyl, C 3
-C
7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well; provided that: when X is 0, B', B 2 and B 3 are each independently selected from C or N, Gq and q are as defined above, W can not be an optionally substituted 3 -pyridazinyl or 4-pyrimidinyl; when X is CH 2 , BI, B2 and B 3 are C and Gq and q are as defined above, W can not be 2-phenyloxazol-4-yl, 4-phenyloxazol-2-yl, 4-(3 (benzyloxy)propyl)-oxazol-2-yl, 4-phenylthiazol-2-yl, 4-methylthiazol 2-yl, benzo[d]oxazol-2-yl or benzo[d]thiazol-2-yl; when X is CH 2
CH
2 , B1, B2 and B3 are C and Gq and q are as defined above, W can not be 4-imidazolyl.
WO 2005/123703 PCT/IB2005/002390 56 In a more preferred aspect of formula II Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a heteroaryl selected from the group of formula: R 2 R 2 R 2 R1R ' RI R 3 R
R
3 -N R N N R N R 1 2 R R1, R2, R3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted CI-C 6 -alkyl,
C-C
6 -alkylhalo, aryl, Co-C 6 -alkyl-OR 5 , Co-C 6 -alkyl-NRR 6 , Co-C 6 alkyl-NRC(=O)-R or Co-C 6 -alkyl-NRsS(=O) 2
-R
6 substituents; R and R 6 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-CG-alkyl, Ci-C 6 -alkylhalo, C 3 C 7 -cycloalkyl, C 3
-C
7 -cycloalkyl-C-C 6 -alky1, heteroaryl, CI-C 6 -alkyl heteroaryl, aryl; X is selected from an optionally substituted C-C 6 -alkyl or C-C 6 alkylhalo; W' is selected from: AW Gq N~ -Gq - N GN -G G groups are each independently selected from the group consisting of hydrogen, halogen, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, Co-C 6 -alkyl-OR 7 , O-Co-C 6 -alkylaryl, heteroaryl, aryl, Co-C 6 alkyl-NR 7 R or Co-C 6 -alkyl-NR 7
-S(=O)
2 R substituents; q is an integer from 1 to 5;
R
7 and R 8 are each independently selected from hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo; Any N may be an N-oxide; The present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. Specifically preferred compounds are: 2-Methyl-(4-(4-phenyl)but-1-ynyl)thiazole WO 2005/123703 PCT/1B20051002390 57 2.-(4-(3-(2-Ethylplienyl)- 1 ,2,4-Oxadiazol-5-yl)b-at- 1 -ynyl)pyridine 2-(4-(Pyridin-2-yl)but-3 -ynyl)isoindolin e- 1,3-dione 2 -(4-{Pyridin-2-yl)but-3-ynyl)phthalazin- 1(2R)-one 2-(4-Phenylbut-1 -ynyl)quinoline 2-(4-Phenylb-ut-1 -ynyl)pyrimidine 2-(4-Phenylbut-1-ynyl)benzo[djoxazole 2-(4-(Pyridin-2-yl)but-3 -ynyl)b eazo [c] oxazole 2 -(4-(Pyridin-2-yl)but-3-ynyl)benzo[i]oxazole hydrochoride 2-(4-(3-(4-Fluorophenyl)-l1 2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3-Phenyl) 1 ,2,4-oxadiazol-5-yl)butl -ynyl)pyridine 2-Methyl-4-(4-phenylbuat- 1-ynyl)- 1H-inidazole N-Methy1-N-phenyl-5-(pyridin-2-y1)pent-4-ynainide N-(4-Fluoropheny)-N-methy-5-rdij2y)pent-4ynarmjde 2-(4-{2-Phenylthiazol-4-yl)but- 1 -ynyl)pyridine 2-(4-(3 -o-Tolyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-benzyl-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(2-Fluorobenzyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(2-Methylbenzyl)- 1,2,4-oxadiazol-5-yl)but- 1 -ynyl)pyridine 2-(4-(3 -(4-Fluorobenzyl> 1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(4-Methoxybenzyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -Isopropyl- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -Butyl- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(3 -Fluorobenzyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(3-Methoxybenzyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(2-Fluorophenyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(3 -Fluorophenyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 5 -Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[ci]oxazole 5-Methyl-(2-(4-pyridin-2-yl)but-3 -ynyl)benzo[d]oxazole 6-Methyl-(2-(4-pyridin-2-yl)but-3 -yny1)benzo[d~oxazole 4 -Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[ci]oxazole 2
-(
4 -(2-Methylthiazol-4-yl)but-3-ynyl)benzo[dgoxazole 2-(4-(5-Pheny1-2H-tetrazo-2-y1)but- 1-ynyl)pyridine
N-(
4 -Fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[cilthiazole 6-Chloro-(2-(4-pyridin-2-yl)but-3 -ynyl)benzo [c] oxazole 5 -Fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 2-(6-(4-Fluorophenyl)hexa- 1,5-diynyl)pyridine 2-(4-(3 -(2-Methoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)but- 1 -ynyl)pyridine 2-(4-(3 -(3 -Methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(4-Methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-mi-Tolyl- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-p-Tolyl- 1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(2-Chlorophenyl> 1 ,2,4-oxadiazol-5-yl)but-l1-ynyl)pyridine 2-(4-(3 -(3 -Chiorophenyl)- 1,2,4-oxadiazol-5-yl)but-l1-ynyl)pyridin~e 2-(4-(3-(4-Chlorophenyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-(2,6-Dimethylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3-(2-Trifluoromethyl)phenyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-(Naphthalen-1 -yl)-1 ,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3-(Naphthalen-2-yl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(2,3 -diinethylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine WO 2005/123703 PCT/1B20051002390 58 2-(4-(3 -(2,5-Dichiorophenyl)- 1 ,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3-(2,5-diinethylphenyl)- 1 ,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3 -(2,6-Dichiorophenyl)- 1 ,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridirie 2-(4-(3-(2,3-dichlorophenyl)-1 ,2,4-oxadiazol-5-yl)hut- 1-ynyl)pyridine 2-(4-(3-(2,4-dicblorophenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(2-chloro-6-methylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3 -(5-Fluoro-2-methylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3 -(5-Chloro-2-methylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(3 -(2-(Trifluoromethoxy)phenyl)-1 ,2,4-oxadiazol-5-y1)but-1 -ynyl)pyridine 6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 7-Chloro-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[d]oxazole 7-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 2-(4-(5-Phenyloxazol-2-yl)but-1 -ynyl)pyridine 2-(4-(3 -(3 -Chloro-2-methylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[dloxazol-4-o 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)benzo[dloxazole 4-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[doxazole 2-.(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[5,4-blpyridine 7-Cbloro-5-fluoro-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo [d]oxazole 2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-Cabottfle 7-Chloro-5-fluoro-2-(4-(2-methylthiazol-4-y)but-3-ylyl)belzo [d]oxazole 7-(Trifluoromethyl)-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[d]oxazole 7-Bromo-5-fluoro-2-(4-(pyridin-2-y)but-3-yny)bezoIdoxazole 5-Fluoro-7-pheny1-2-(4-(pyridin-2-y)but-3-yny)bezo[doxazole 2-(4-(2-Chloropyrimidin-4-yl)but-3-ynyl)benzo[dloxazole 2-Chloro-4-(4-phenylbut-1 -ynyl)pyrinaidine 4-Bromo-2-(4-(pyridin-2-yl)but-3-ynyl)bezo[d]oxazole 4-Pheny1-2-(4-(pyridin-2-y)but-3-yny)benzo[doxazole 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[doxazole 5,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[doxazole 4-Fluoro-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[d]oxazole 7-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[djoxazole-7-carbonitrile 7-hoo4fur--4(yii--lbt3yy~ez~~xzl 7-Methoxy-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[djoxazole 7-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzoI~d]oxazole 4,7-Difluoro-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[djoxazole 7-F1luoro-4-(trifluorometl)-2-(4-(pyidil-2-y)but-3-yl)belzo [d]oxazole 2-(4-(Pyrimidin-4-yl)but-3 -ynyl)benzo[d]oxazole N-(3-Chlorophenyl)-N-methyl-5-(pyridin-2-y)pelt-4-ylalfde 7-Chloro-4-tnethyl-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[d]thiazole 4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)belzo[d]tiazole 4,7-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)belzo [dithiazole 4.-Methyl-2-(4-(pyridin-2-yl)but-3 -ynyl)benzofldjthiazole 5-Fluoro-2-(4-(pyridin-2-y)but-3-yl)bezo[dtflazole 4-Cliloro-2-(4-(pyridin-2-yl)but-3 -ynyl)benzolld]thiazole N-(2-Chlotopheny1)-N-methy1-5-(pyridifl-2-y1)pelt-4-ylamide 1-Methyl-2-(4-(pyridin-2-yl)but-3 -ynyl)- 1H-benzo[d]imidazole 2-(4-(Pyriclin-2-yl)but-3 -ynyl)-211-indazole WO 2005/123703 PCT/1B20051002390 59 1 -(4-(pyridin-2-yl)but-3-ynyl)-1ll-indazole 2-(4-(5-Phenyl-1H-pyrazol- 1-yl)but-1 -ynYl)pyridine 2-{4-(3 -Phenylisoxazol-5-yl)but- 1-ynyl)pyridine 2-(4-(2-Methyhthiazol-4-yl)but-3 -ynyl)benzo[d]thiazole 2-(4-(5-Fhioropyridin-2-yl)but-3-YnYl)benzo[d]thiazole 2-{4-(6-Methylpyridin-2-yl)but-3-ynyl)benzo [d]thiazole 2-(4-(6-C111oropyridin-2-y1)but-3-YnY1)benzo[dlthiazole 7-Chloro--4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo [d]thiazole 2-(4-(6-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole 2-(4-(Pyridin-2-yl)but-3-ynyl)quinoline 2.-(4-(4-Phenyl- 1H-pyrazol- 1 -yl)but-1 -ynyl)pyridine 7-Cliloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole 2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-indazole 1 -(6-(pyridin-2-yI)hex-5-ynyl)-1H-indazole 2-(4-(6-(IFluoromethyl)pyridin-2-yl)but-3 -ynyl)quinoline 2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)quinoline 2
-(
4
-(
6 -(Fluorornethyl)pyridin-2-yl)but-3-ynyl)quinoxaline 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole 2-(4-(4-(4-Fl-uorophenyl)- 1H-pyrazol-1 -yl)but- 1-ynyl)pyridine 2-(4-(4-o-Tolyl-1H-pyrazol-1 -yl)but-1 -ynyl)pyridine 2-(Fluoromethyl)-6-(4-(4-o-tolyl- 1H-pyrazol- 1-yl)but-1 -ynyl)pyridine 2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)- 1H-pyrazol- 1-y1)buat- 1-ynyl)pyridine 6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)b-ut-3-ynyl)quinoxaline 6,7-Difluoro-2-(4-(6--(fluoromethy1)pyridin-2-y1)but-3-ynyl)quinoxaline 4-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 -ynyl)-2H-indazole 4-Cliloro-2-(4-(pyridin-2-yl)but-3 -ynyl)-2H-indazole 6-IFluoro-2-(4-(6-(fluoromethyt)pyridin-2-yl)but-3 -ynyl)-2H-indazole 4-Cbloro-2-(4-(6-(fluoroniethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole 7-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-yniyl)-2H-indazole 2-(4-(3 -Phenyl- 1H-pyrazol- 1 -yl)but-I -ynyl)pyridine 2-(4-(3 -(4-Fluorophenyl)isoxazol-5-yl)but- 1-ynyl)pyridine 2-(4-(5-(4.-Fluorophenyl)-1H-pyrazol- 1-yl)but- 1-ynyl)pyridine 2-(1 -Fluoro-4-(pyridin.-2-yl)but-3-ynyl)quinoxaline 2.-(4-(3 -Methyl-4-phenyl- 1H-pyrazol- 1 -yl)but-1 -ynyl)pyridine 2-(4-(5-methyl-4-phenyl-l1H-pyrazol- 1-yl)but- 1-ynyl)pyridine 2-(4-(4-(4-Fluorophenyl)- 1H-i ,2,3 -triazol- 1-yl)but- 1-yjLiyl)pyridine 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-3-methyiquinoxaline 2-(4-(Pyridin-2-yl)but-3 -ynyl)isoquinolin-1 (2H)-one 2,6-Dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 2,6-Difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)pent-4-ynamide 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindolin- 1 -one N-(2-Fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide N-(3-Fluorophenyl).-5-(pyridin-2-yl)pent-4-ynainide N-(4-Fluoro-2-methyl-phenyl)-5-(pyridin-2-yl)pent-4-ynamide 2,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzainide 2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 -ynyl)benzaraide 2-Ghloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzenesulfonamide 2.-Chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonarnide 5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluoro--2-inethyl-phenyl)pent-4-ynamide WO 2005/123703 PCT/1B20051002390 60 5-(4-Fluoro-phenyl)-l1-(4-pyridin-2-yl-but-3 -ynyl)-l H-pyridin-2-one 2-(Fluoromethyl)-6-(4-(4-(4-fl-uorophenyl)- 1 11-1 ,2,3-triazol- 1 -yl)but- 1 -ynyl)pyridine 2-(4-(4-(4-Fluorophenyl)-2H-1 ,2,3-triazol-2-yl)but- 1 -ynyl)pyridine 2-(Fluoromethy1)-6-(4-(4-(4-fluoropheny1)-2H-1 ,2,3-triazol-2-yl)but- 1-ynyl)pyridine 2-(4-(4-(4-Fluorophenyl)-5-methyl-2H- 1,2,3 -triazol-2-yl)but-1 -ynyl)pyridine 2-(4-(4-(4-Fluorophenyl)-5-methyl-lH- 1,2,3 -triazol- 1 -yl)b-ut-l1-ynyl)pyridine 2-(4-(4-(2-Cblorophenyl)-2-H-1 ,2,3-triazol-2-yl)but- 1-ynyl)pyridine 1 -(4-(4-(2-Cblorophenyl)- 1H- 1,2,3-triazol-2-yl)but-1-ynyl)pyridine 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)- 1 -methyl-i H-benzo~d]imidazole 7-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)- 1 -methyl-1H benzo[d]imidazole 7-Cbloro-1 -methyl-2-(4-(pyridin-2-yl)but-3 -ynyl)-l1I-benzo[d]imidazole 4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl- IN benzo[d]imidazole 1 -Isoprcopyl-2-(4-(pyridin-2-yl)but-3-ynyl)- 1 H-b enzo Ldlimidazole 1 -Phenethyl-2-(4-(pyridin-2-yl)but-3 -yny1)-1H-benzo~d]imiidazole 1 -Benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole 5-Fluoro- 1-methyl-2-(4-(pyridin-2-yl)but-3 -ynyl)- 1H-benzohdlimidazole 1 -(4-(Pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one 3 -Methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamnide 3 -Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide N-Methyl-2-phenyl-N-(4-(pyridin-2-yl)but-3 -ynyl)acetamide N-Methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide 4-Fluoro-N-rnethyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamnide 2-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 3 -Cliloro-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide 4-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzenesulfonamide 2-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide 2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide 2-Cbloro-'N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzene sulfonamide 2,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide N-Methyl-N- (4-(pyridin-2-yl)but-3 -ynyl)benzan-ide N,2-Dimethyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide 2-Fluoro-N-methyl-N-(4-(pyridin-2-yl)b-ut-3 -ynyl)benzaniide N,4-Dimnetliyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide N,3 -Dimethyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide 2-Methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide 2,3-Difiuoro-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide 2,6-Dichloro-N-methy1-N-(4-(pyridin-2-y1)but-3-ynyl)benzamiide N,3 ,5-Trimethyl--N-(4-(pyridin-2-yl)but-3 -ynyl)isoxazole-4-sulfonamide N-(4-(Pyridin-2-yl)but-3-ynyl)benzold]thiazol-2-amine 1 -Methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-l1H-benzo[d]iinidazol-2(3H)-one (3-Fluoropyridin-2-yl)but-3-ynyl)benzo [d] oxazole 2-(4- (2-Methyl- 1H-imidazol-4-yl)but-3 -yny1)benzo~d]oxazole 2-(4-(1 ,2-Dimethyl- 1H-imidazol-4-yl)but-3 -ynyl)benzo [d]oxazole 4-(Pyridin-2-yl)but-3-ynyl 2-chlorobenzoate 4-(Pyridin-2-yl)but-3-ynyl 3 -chiorob euzo ate 3-Chiorophenyl 5-(pyridin.-2-yl)pent-4-yno ate 3-Chiorophenyl 5-(3 -fluoropyridin-2-yl)pent-4-yno ate WO 2005/123703 PCT/1B20051002390 61 2-Chiorophenyl 5-(pyridin-2-yl)pent-4-ynoate 2-Chlorophenyl S-(2-methylthiazol-4-yl)pent-4-ynoate 2 -(4-(6-(Fluoromethyl)pyridin-2-yl)but-3 -ynyl)benzo [djthiazole 2
-(
5 -(Pyridin-2-yl)pent-4-ynyl)isoindoline-1,3 -dione 2
-(
6 -(Pyridin-2-yl)hex-5-ynyl)phthalazin- 1 (2H)-.one 1 -Methyl-3-(5-(pyridin-2-yl)pent-4ynyl)- 1H-benzo[d]iniidazol-2(3H)-one N-4Clrpey)5(yii--lpn--nmd
N-(
3 -Chlorophenyl)-5-(pyridin-2-y)pent4ynamide
N-(
2
,
4 -Difluorophenyl)-5-(pyridin-2-y)pent4ynamide 2-(4-(Pyridin-2-yl)but-3-ynyl)-im-idazo[1 ,2-a]pyridine 8-ehl2(-pyii- lbt3-nl-mdz[,2-a]pyridine 5-Methy1-2-(4-(pyridin-2-y)but-3-yny1>-inidazo [1 ,2-a]pyridine 5-Phenyl-2-(4-(pyridin-2-yl)but-3 -ynyl)-imidazo[ 1,2-a]pyridine 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)irTnidazo [1 ,2-a]pyridine 6 -Fluoro-2-(4-(pyridin-2-y)but-3-yny1)4miidazo[1 ,2-a]pyridine 2
-(
4 -(5-Fluoropyridin-2-y)but-3-yny1)-ipdazo[ 1,2-ajpyridine 2-(4-(Pyridin-2-yl)but-3 -ynyl)-211-benzo[d] [1,2,3 Itriazole 1 -(4-(pyridin-2-yl)but-3 -ynyl)- 1H-benzo[d] [1 ,2,3]triazole 2-(4-(Pyridin-2-y1)but-3-yny)-2H-benzo[dj[1,2,3 ]triazole hydrochloride 2-(5-(Pyridin-2-yl)pent-4-ynyl)-2H-benzo[d] [1 ,2,3]triazole 1 -(S(Pyridin-2-yl)pent-4-ynyl)-l1H-benzo[dj [1 ,2,3]triazole 1 -(6-(Pyridin-2-yl)liex-5-ynyl)- 1H-benzo[d] [1,2,3 ]triazole 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H--benzo[d] [1,2,3 ]triazole 5-loo2(-prii-- bt3ynl-Hbnod[1 ,2,3]triazole 2-4(-Furmtylprdn2y u-3yy)2-eiod[1,2,3 ]triazole 2 -(4-(6-(Fluoromethyl)pyridin-2-y1)but-3-yny)2Hbezo [d] [1,2,3 ]triazole hydrochloride 4 ,6-Difluoro-2-(4-(6-(fluoromethy)pyridin2-.y)bu-3 -ynyl)-2H benzo[d] [1 ,2,3]triazole 4
,
6 -Difluoro-2-(4-(6-(fluoromethyl)pyridin2yl)but-3-ynyl)-2H benzo[d] [1 ,2,3]triazole hydrochloride 4
,
5 -Difluoro-2-(4-(6-(fluoromethyl)pyridin2yl)but-3-ynyl)-2H benzo[dj [1 ,2,3]triazole 4 ,5-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-y1)but-3-ynyl)-2H benzo[dj [1 ,2,3]triazole, hydrochloride 2-(4-(6-(Difluoromethy)pridin-2y)but3yny)2Hbenzo[Jj [1,2,3 Itriazole 4,-iloo2(-(yii- lbt3-nl-Hbnod[1,2,3 ]triazole 4
,
5 -Difluoro-2-(4-(pyridin-2-y)but-3-yny)2H-.benzo[dg [1,2,3 Itriazole 2-4(-ehlyii-- ~u--nl-Hbnod[1 ,2,3]triazole 2-(4-(3 -Fluoropyridin-2-yl)but-3 -ynyl)-2H-benzo [d][l ,2,3jtriazole 5-Fluoro-2-(4-(6-(fluoromehyl)pyridin-2-y)bu-3 -ynyl)-2H-benzo[d] [1 ,2,3]triazole 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)-2H-benzo [JJ[1 ,2,3]triazole 4-Chloro-2-(4-(pyridin-2-yl)but-3 -ynyl)-211-benzo[d] [1 ,2,3]triazole 4-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-ylybu-3 -ynyl)-2H-benzo[d] [1 ,2,3]triazole 5,6-Difluoro-2-(4-(pyridin-2-yl)but-3 -ynyl)-211-benzo[d] [1,2,3 Itriazole 5
,
6 -Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H benzo[d] [1,2,3]triazole 4-Cbloro-2-(4-(1 -methyl- ll-pyrazol-3-y)but-3-yny)-2E1-benzo[d] [1 ,2,3]triazole 6-(4-(4,6-Difluoro-2H-benzo[dj [1 ,2,3]triazol-2-yl)but- 1-ynyl)pyridin-2-amine 2-(4-(2H-Benzo [d] [1,2,3 jtriazol-2-yl)but-1 -ynyl)-6-niethylpyridin-3 -amine WO 2005/123703 PCT/IB2005/002390 62 4 -Nitro-2-(4-(pyridin-2-y)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 2
-(
4 -(6-(Fluoromethyl)pyridin-2-yl)but-3 -ynyl)-4-nitro-2H-benzo [d] [1,2,3]triazole 2 -(4-(Pyridin-2-yl)but-3 -ynyl)-2H-benzo[d] [1,2,3]triazol-4-amine 4 -Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-methyl-2H-benzo[d][1,2,3]triazole 2-(4-(6-(Fluoromethy1)pyridin-2-yl)but-3 -ynyl)-5-methyl-2H-benzo[d] [ 1, 2 ,3]triazole 5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 6-(4-(2H-Benzo[d] [1,2,3]triazol-2-yl)but-1 -ynyl)-N-methylpyridin-2-amine N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)acetamide 6-(4-(2H-Benzo[d] [1,2,3 ]triazol-2-yl)but-1 -ynyl)-N-ethylpyridin-2-amine N-(6-(4-(2H-Benzo[d] [1,2,3]triazol-2-yl)but-1 -ynyl)pyridin-2-yl)methylsulfonanide N-(6-(4-(2H-Benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)formamide 4-Chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-yny)-2H benzo[d][1,2,3]triazole 4,5-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 2
-(
4
-(
6 -(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4,5-dimethyl-2H benzo[d] [1,2,3]triazole 2
-(
4 -(6-Chloropyridin-2-yl)but-3-ynyl)-2H-benzo[d] [1,2,3]triazole 2-(4-(6-(1 -Fluoroethyl)pyridin-2-yl)but-3 -ynyl)-2H-benzo[d] [1,2,3]triazole 2
-(
4 -(4,5-Dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 2
-(
4 -(Pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 2
-(
4 -(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-[1, 2
,
4 ]triazolo[4,3-a]pyridin-3 (2H) one 2
-(
4
-(
4 -Methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 8 -Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 8-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 6 -Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine 6 -Fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 8-Bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 8-(Benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-y1)but-3-ynyl)-imidazo[1,2-a]pyridine 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine 6,8-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-inidazo[1,2-a]pyridine 6
,
8 -Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-iidazo[1,2-a]pyridine The present invention relates to the pharmaceutically acceptable acid addition salts of compounds of the formula (I) or pharmaceutically acceptable carriers or excipients. The present invention relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 antagonists. The present invention relates to a method useful for treating or preventing peripheral and central nervous system disorders selected from the group consisting of: substance tolerance or dependence, anxiety disorders, depression mood disorders, psychiatric disease such as psychosis, inflammatory or neuropathic pain, Fragile X syndrome, autism, memory deficits, Alzheimer's disease, Parkinson's disease, migraine, ischemia, drug abuse and addiction.
WO 2005/123703 PCT/IB2005/002390 63 The present invention relates to pharmaceutical compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose. The compositions may be administered by any suitable route. For example orally in the form of capsules, etc..., parenterally in the form of solutions for injection, topically in the form of onguents or lotions, ocularly in the form of eye-drops, rectally in the form of suppositories, intranasally or transcutaneously in the form of delivery system like patches. The pharmaceutical formulations of the invention may be prepared by conventional methods in the art; the nature of the pharmaceutical composition employed will depend on the desired route of administration. The total daily dose usually ranges from about 0.05 - 2000 mg. METHODS OF SYNTHESIS Compounds of general formula I may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Green T.W. and Wuts P.G.M. (1991) Protecting Groups in Organic Synthesis, John Wiley et Sons ). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of process as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula I. The compound of formula I may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or S-enantiomers. If for instance, a particular enantiomer of the compound of formula I is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provided the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, this resolution may be conveniently performed by fractional crystallization from various solvents, of the salts of the compounds of formula I with optical active acid or by other methods known in the literature, e.g. chiral column chromatography. Resolution of the final product, an intermediate or a starting material may be performed by any suitable method known in the art as described by Eliel E.L., Wilen S.H. and Mander L.N. (1984) Stereochemistry of Organic Compounds, Wiley Interscience. Many of the heterocyclic compounds of formula I can be prepared using synthetic routes well known in the art (Katrizky A.R. and. Rees C.W. (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press). The product from the reaction can be isolated and purified employing standard techniques, such as extraction, chromatography, crystallization, distillation, and the like. The compounds of Formula I may be prepared by general route of synthesis as disclosed in the following methods.
WO 2005/123703 PCT/IB2005/002390 64 The compounds of formula II-BI wherein W and G 1 are as described above,
B
1 is N and X is C 1
-C
6 alkyl may be prepared according to the synthetic sequences illustrated in the Schemes 1-3. Scheme 1 Base NH 2 Gi--N + H 2 N-OH G N--OH In the turn, an nitrile derivative (for example 4-Fluoro-benzonitrile) is reacted with hydroxylamine under neutral or basic conditions such as triethylamine, diisopropyl-ethylamine, sodium carbonate, sodium hydroxyde and the like in a suitable solvent (e.g. methyl alcohol, ethyl alcohol). The reaction typically proceeds by allowing the reaction temperature to heat slowly from ambient temperature to a temperature range of 70'C up to 80 0 C for a time in the range of about 1 hour up to 48 hours inclusive (see for example Lucca, George V. De; Kim, Ui T.; Liang, Jing; Cordova, Beverly; Klabe, Ronald M.; et al; J.Med.Chem.; EN; 41; 13; 1998; 2411 2423, Lila, Christine; Gloanec, Philippe; Cadet, Laurence; Herve, Yolande; Fournier, Jean; et al.; Synth.Commun.; EN; 28; 23; 1998; 4419-4430 and see: Sendzik, Martin; Hui, Hon C.; Tetrahedron Lett.; EN; 44; 2003; 8697-8700 and references therein for reaction under neutral conditions). Scheme 2 NH +HO X
NH
2 csaon G N-OH XO i G O G - X The substituted amidoxime derivative (described in the scheme 1) may be converted to an acyl-amidoxime derivative using the approach outlined in the Scheme 2. The coupling reaction may be promoted by coupling agent known in the art of organic synthesis such as EDCI (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide), DCC (NN'-Dicyclohexyl-carbodiimide), in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, NN-dimethylformamide, dioxane) Typically, a co-catalyst such as DMAP (NN-dimethylaminopyridine) will also be present in the reaction mixture. The reaction typically proceeds at ambient temperature for a time in the range of about 4 hours up to 12 hours to produce the intermediate acyl-amidoxime. The cyclisation reaction may be effected thermally in a temperature range of about 80'C up to about 1501C for a time in the range of about 2 hours up to 12 hours (see for example Suzuki, Takeshi; Iwaoka, Kiyoshi; Imanishi, Naoki; Nagakura, Yukinori; Miyata, Keiji; et al.; Chem.Pharm.Bull; 47; 1; 1999; 120 - 122). The product from the reaction can be isolated and purified employing standard techniques, such as extraction, chromatography, crystallization, distillation, and the like. The scheme 3 illustrates the preparation of compounds of formula H-BI by reacting an alkyne derivative (described in the scheme 2), with a substituted 5-, 6 heterocyclic containing a N adjacent to the leaving group L 1 for example 2-iodo pyridine. Thus in Scheme 3, L 1 includes halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl. This general route of synthesis has been described in J. Med. Chem. 2000, 43, 4288-4312.
WO 2005/123703 PCT/IB2005/002390 65 Scheme 3 -N S onogashira X4 "OP 0 -N L1 N X - G This palladium catalyzed C-C coupling reaction requires a catalyst such as PdCl 2 (PPh 3
)
2 , Pd(PPh 3
)
4 , Pd(OAc) 2 or Pd on carbon in a suitable solvent like DMF, acetonitrile or benzene. Typically a co-catalyst such as copper(I) iodide and a base (e.g., triethylamine, diisopropylamine, KOAc...) will also be present in the reaction mixture. The coupling reaction typically proceeds by allowing the reaction temperature to warm slowly from about 0' up to ambient temperature, or heated to a temperature anywhere between 30'C and 150'C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 1 up to 24 hours, with about 12 hours typically being sufficient. The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, sublimation, and the like. In another embodiment of the present invention, compounds of formula I-BI may be prepared according to the synthetic sequences illustrated in the Schemes 4-5. Scheme 4 LO-PG 1 Sonogashir
PG
1 Deprotection 0I 0 -n OH -- O A substituted 5-, 6- heterocyclic containing a N adjacent to the leaving group
L
1 is reacted with an alkyne derivative, in a manner similar to the procedure presented for Scheme 3. Thus in Scheme 4, L 1 includes halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl. Protecting goups PG 1 are removed using standard methods to produce a carboxylic acid derivative. Scheme 5 OH HO-N ,0csatio" O-N (Dw- , + \\ -G' y W - X4 G 0 H 2 N N Referring to scheme 5, the di-substituted oxadiazole is prepared as described in scheme 2 from a suitable amidoxime precursor. The compounds of formula II-C wherein W and B 1 , B 2 , B 3 , and Gq are as described above and X is CH 2
-R
9 C(=O) may be prepared according to the synthetic sequences illustrates in the Schemes 6-7.
WO 2005/123703 PCT/IB2005/002390 66 Scheme 6 0 B Couplin )3 2
:B
1 B3 N + HO 3 N Gq /0 G R In turn, the pentynoic acid may be converted to aide derivative using the approach outlined in the Scheme 6. The reaction may be promoted by a coupling agent known in the art of organic synthesis such as EDCI (1-(3 Dimethylaminopropyl)-3-ethylcarbodiimide), DCC (NN'-Dicyclohexyl carbodiimide), in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N dimethylformamide, dioxane) Typically, a co-catalyst such as HOBT (Hydroxybenzotriazole) will also be present in the reaction mixture. The reaction typically proceeds at ambient temperature for a time in the range of about 4 up to 12 hours. Scheme 7 illustrates the final synthetic step. Scheme 7 0 0 Sonogashira B =B2 LR B 3 NRN
B
3 R9 N- GGq The alkyne product from the reaction in Scheme 7 may be prepared using the approach outlined in Scheme 3. Thus, in Scheme 7, L 1 includes halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl. The compounds of formula I-C wherein W and B 1 , B 2 , B 3 , and Gq are as described above and X is - may be prepared according to the synthetic sequences illustrated in the Schemes 8-10. Scheme 8 B:B3 L1S+onogashira : B G / G 1 OOH~ GqOH Pd' q / O I Halogenatlon B31 Gq L2 The substituted propargylic alcohol intermediate from the reaction in Scheme 8 may be prepared using the approach outlined in Scheme 3. The substituted propargylic alcohol derivative may be subsequently converted into the corresponding propargylic halide derivative according to the method illustrated in J.Med.Chem., 2000, 48, 8, 1508-1518. The halogenation reaction may be promoted by a mixture of halogenating reagent (for example carbone tetrabromide, WO 2005/123703 PCT/IB2005/002390 67 PPBr 3 , SOC1 2 , PC1 5 , POC1 3 and the like) in a suitable solvent (e.g. dichloromethane, tetrahydrofuran, diethylether, toluene). If required a co-reagent, such as triphenylphosphine, will also be present in the reaction mixture. The reaction is typically allowed to proceed by maintaining at room temperature for a time in the range of about 2 hours up to 4 hours. Thus, in Scheme 8, Li includes halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl. And L 2 is halides such as Cl, Br, I. Scheme 9 B2=B B2=B G- L Gi ---- 2
B
Deprotection B2B Gq The substituted propargylic halide intermediate from the reaction in Scheme 8 may be transformed into bis-acetylenic derivatives using the approach outlined in Scheme 9. An appropriate aryl- or heteroaryl-alkyl halide derivative is converted into the corresponding butynyl derivative according to the method illustrated in Tetrahedron, 1999, 55, 49, 13907-13926. The alkylation reaction may be promoted by a mixture of trimethyl(prop-l-ynyl)silane and an organolithium reagent such as n-butyllithium, tButyllithium and the like which is capable of undergoing metal exchange reaction in a suitable solvent (e.g. tetrahydrofuran, diethylether), at an appropriate temperature, usually between about -78'C and 0 0 C, followed by condensation of aryl- or heteroaryl-alkyl halide derivatives. Protecting goup trimethylsilyl is removed under basic condition such as NaOH, KOH, K 2
CO
3 or nBu 4 F and the like according to standard methods familiar to those skilled in the art (J.Org.Chem., 2003, 68, 4, 1376-1385). The reaction typically proceeds by allowing the reaction temperature to warm slowly from ambient temperature to 650C for a time between lh and 24 hours in a suitable solvent (e.g. methyl alcohol, ethyl alcohol, tetrahydrofuran, diethylether). Thus, in Scheme 9, L 2 includes halides such as Cl, Br, I or trifluoromethanesulfonyl. Scheme 10 BB1=13 B'=B2 \B3
B
3 Sonogashira
L
3 PdO The bis-acetylenic derivative from the reaction in Scheme 9 may be prepared using the approach outlined in Scheme 3. Thus, in Scheme 10 L 3 includes halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl.
WO 2005/123703 PCT/IB2005/002390 68 The compounds of formula I1-A2 wherein W, G, G2, G 3 , G4 and G 5 are as described above, X is CH 2 may be prepared according to the synthetic sequences illustrates in the Schemes 11-14 In accordance with the present invention, imidazopyridine derivatives can be prepared by methods known in the art (A. R. Katrizky A.R. and C. W. Rees (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press). Scheme 11 LG2G 1
G
2 G1 G 2
G
1 o + N G G 3 o / N 2 G 3 Reduction / N 2G3 0 O H 2 N G4 0 N HD N G
PG
1 G PG 1 G5 G 5 D Halogenation G1 -- G 2 /N G 3
L
2 N 4
G
5 Referring to scheme 11, a substituted aminopyridine derivative D (prepared using synthetic chemistry techniques well known in the art) is reacted with an a-halo ketoester in a suitable solvent (e.g. EtOH, MeOH, THF, acetone, CH 3 CN and the like) at temperature between 50'C to 90'C for 5h to 12h, to form a substituted imidazopyridine, according to the method illustrated in J.Med.Chem., 1988, 31, 11, 2221-2227. The resulting imidazopyridine bearing a carboxylic ester group is converted into an alcohol by reacting with a reductive agent such as LiAlH 4 , BH 3 and the like in a suitable solvent (e.g. THF, diethylether) for a period of time sufficient to proceed to completion, typically from about 1h to 12h, at ambient temperature being advantageous (see for example J.Heterocycl.Chem., 1988, 25, 129-137). The heterocyclic alkyl-alcohol derivative may be subsequently converted into the corresponding heterocyclic alkyl-halide derivative according to the method illustrated in J.Med.Chem., 2000, 48, 8, 1508-1518. The halogenation reaction may be promoted by a mixture of halogenating reagent (for example carbone tetrabromide, PBr 3 , SOC1 2 , PC1 5 , POC1 3 and the like) in a suitable solvent (e.g. dichloromethane, tetrahydrofuran, diethylether, toluene). If required a co-reagent, such as triphenylphosphine, will also be presented in the reaction mixture. The reaction is typically allowed to proceed by maintaining at room temperature for a time in the range of about 2 hours up to 4 hours. Thus, in Scheme 11, L 1 includes halides such as Cl, Br, I and PGi includes Methyl, ethyl, isopropyl, tert-Butyl or benzyl and the like. In another embodiment of the present invention, depicted in Scheme 12, substituted imidazopyridine alkyl-halide derivatives may be prepared from a bis-a haloketone and a substituted aminopyridine D according to standard methods familiar to those skilled in the art (J.Heterocyclic.Chem., 1988, 25, 129-137).
WO 2005/123703 PCT/IB2005/002390 69 Scheme 12 L G2 G 1
G
2 O+ N G3N G
H
2 N G N G4 L2 G4 G D (35 G35 The reaction typically proceeds by allowing the reaction temperature to heat slowly from ambient temperature to 65'C for a time between 1h and 12 hours in a suitable solvent (e.g. methyl alcohol, ethyl alcohol, tetrahydrofuran, diethylether, acetone and the like). Thus, in Scheme 12, L 2 includes halides such as Cl, Br, I. Scheme 13 G32 G 1 G33 G 2 G 1 / G L2 Base
G
5 GsN Deprotection G2 G' G3N G34 ~N E G E G35 Thus, in the Scheme 13, a substituted imidazopyridine alkyl-halide intermediate may be transformed into a mono substituted acetylenic derivative using the approach outlined in Scheme 9 to produce the compound E. Thus, in Scheme 13, L 2 includes halides such as Cl, Br, I. Scheme 14 G31 G 2
G
1 G32( + N 3 Sonogashira G3 La Pdu F E N G4 G4 G5 G5 The bis-substituted alkyne product from the reaction in Scheme 14 may be prepared using the approach outlined in Scheme 3. Thus, in Scheme 14 L 3 includes halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl. In accordance with the present invention, imidazopyridine derivatives can be prepared also using the approach outlined in Scheme 15-17 Scheme 15 WO 2005/123703 PCT/IB2005/002390 70 L 1 Base
G
1 Ring opening G ' Si _ + Si 71 -L / / / B OH Oxydation Si L2 C 0 Thus, in the Scheme 15, an appropriate epoxyde-alkyl halide derivative (e.g., 2-(chloromethyl)oxirane) is converted into the corresponding butynyl derivative A according to the method illustrated in the Scheme 9. The resulting substituted acethylenic intermediate A may be subsequently converted into the intermediate B according to the method illustrated in S. Hoarau et al., Tetrahedron Asymmetric. 1996, 7, 2585-2593 and in Gene W. Holbert et al., Tetrahedron, 1984, 40, 1141-1144. The ring opening may be promoted by LiBr or KBr and the like in the presence of acetic acid, in a suitable solvent (e.g. mixture tetrahydrofuran and water), at room temperature for a time in a range of about 5 hours up to 12 hours.. In another embodiment of the present invention, depicted in Scheme 15, the intermediate B may be transformed into the corresponding a-halo-ketone C according to the method illustrated in W. Holbert et al., Tetrahedron, 1984, 40, 1141-1144. The oxidation reaction may be promoted by using oxidative agent such as Jone's reagent (CrO 3
/H
2
SO
4 ), TEMPO, PCC and the like by maintaining at room temperature for a time in the range of about 1 hour up to 2 hours. Thus, in Scheme 15, LI L 2 include halides such as Cl, Br, I. Scheme 16 G1 G2G 3 G, G 2 3 S L2L H 2 N N siG intermediate C G6
G
5 D Deprotection
G
1
G
2 E N-(G4
G
5 Thus, in the Scheme 16, an appropriate a-halo-ketone C is converted into the corresponding imidazopyridine E according to the cyclisation method illustrated in the Scheme 11. Protecting group trimethylsilyl is removed under basic condition such as NaOH, KOH, K 2
CO
3 or nBu 4 F according to the method illustrated in the Scheme 9.
WO 2005/123703 PCT/IB2005/002390 71 Scheme 17 ( GIG2 G( 3 Sonogashira N G 2 G 3 L Pd/ L3': G-- 4 G4 F E G5 G The alkyne products from the reaction in Scheme 17 may be prepared using the approach outlined in Scheme 3. Thus, in Scheme 17 L 3 includes halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl. The compounds of formula 1-Al wherein W, G', G 2 , G 3 , G 4 and G' are as described above, X is CH 2 , B 1 , B 2 is C and B 3 is N which may further be substituted by Gq group, may be prepared according to the synthetic sequences illustrate in the Schemes 18-20. Scheme 18 G2 G1 G2 G1G F G3 SNAr HN Reduction HN G 3 G'NH2 + 0 G4 ~N G4 H 2 N G4 o G 5 0 G5 G5 Referring to scheme 18, 1-fluoro-2-nitrobenzene derivative is reacted with a excess of appropriate substituted amine in suitable solvent (e.g. EtOH, MeOH, THF, acetone, CH 3 CN and the like) at temperature between 50'C to 90'C for a time in the range of about 5h up to 12h, to forn a N-substituted-2-nitrobenzenamine according to the method illustrated in Tetrahedron Letters, 2002, 43, 7303-7306. The N-substituted-2-nitrobenzenamine may be subsequently converted into the corresponding N-substituted-benzene-1,2-diamine derivative according to the method known in the art. The reduction reaction may be promoted by 10%Pd/C in a presence of hydrogen source (H 2 , HCOONH 4 , HCOOH, NaBH 4 and the like) or by the presence of metal such as Zinc, Iron and the like in acidic condition (concentrated HC1, H 2
SO
4 or AcOH) in a suitable solvent (e.g MeOH, AcOH, EtOH). The reaction is typically allowed to proceed by maintaining at room temperature for a time in the range of about 2 hours up to 4 hours. Scheme 19 G21 2 G1 G 2 HN 3 0 Cyclisation N G + ak L H N0 G "1L N G 4
H
2 N ,4 G5 Referring to scheme 19, a N-substituted-benzene-1,2-diamine derivative is reacted with an c-halo-carboxylic ester or an a-halo-carboxylic acid (X is selected from Cl, Br, I, and PG 1 includes Methyl, ethyl, isopropyl, tert-Butyl or benzyl and the like) to form an substituted benzimidazole, according to the method illustrated in J. Heterocyclic. Chem., 1983, 20, 1481-1484.
WO 2005/123703 PCT/IB2005/002390 72 The reaction typically proceeds by allowing the reaction temperature to heat slowly from ambient temperature to 9 0 'C in acidic condition (aqueous HCl and the like) for a time between 5h and 12 hours. Scheme 20 G1 G2 G 1
G
2 N
G
3 Base i
-G
3 -S~ + 4 Gs G U 2 N G 4 -S - N G!
G
5 Deprotection
G
1
G
2 N G 3 :- N G4
G
5 Thus, in the Scheme 20 a substituted imidazopyridine alkyl-halide intermediate may be transformed into a mono substituted acetylenic derivative using the approach outlined in Scheme 9. Thus, in Scheme 20 L 2 includes halides such as Cl, Br, I. The compounds of formula 11-B wherein W, Z 9 , Z 10 , Zu, Z1 2 are as described above and X is CI-C 3 -alkyl may be prepared according to the synthetic sequences illustrate in Scheme 21-23. Scheme 21 Gq Sonogashira Z9-- Z W L 1 + W - +1 X-OH Pd* X-OH HN2Z12 Mitsunobu . __ xX-NI Z-ZGq zuzil In Scheme 21, a substituted 5-, 6-heterocyclic containing containing an N adjacent to the leaving group L, is reacted with acethylenic alcohol under Sonogashira condition as illustrated in Scheme 3 to produce a substituted acethylenic alcohol. The resulting alcohol is reacted with a heterocyclic ring containing an acidic NH, under Mitsunobu conditions according to the method illustrated in M.S. Malamas, J. Sredy, I. Gunawan, B. Mihan, D.R. Sawicki, L. Seestaller, D. Sullivan, B.R. Flam, J. Med. Chem. 2000, 43, 995-1010. The Mitsunobu reaction may be promoted by a reagent such as diethylazodicarboxylate, di-tert-butylazodicarboxylate and the like in the presence of triphenyphosphine, in a suitable solvent (e.g. tetrahydrofuran), at an appropriate temperature. Subsequent deprotection of the trimethylsilyl group WO 2005/123703 PCT/IB2005/002390 73 according to the method illustrated in Scheme 9 and cross coupling afforded a compound of formula 11-B. Thus, in Scheme 21, L, may be a good leaving group capable of undergoing a Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonate and the like. In another embodiment of the present invention, depicted in Scheme 22, a acetylenic alcohol may be transformed into the corresponding halide derivative, wherein L 1 is Cl, Br or I, according to the method illustrated in G.C. Crawley, R.I. Dowell, P.N. Edwards, S.J. Foster, R.M. MeMillan, J. Med. Chem. 1992, 35, 2600 2609. The halogenation reaction may be promoted by a mixture of halogenating reagents (for example Br 2 , carbone tetrabromide, PBr 3 , SOC1 2 , PCl 5 , POC1 3 and the like) in a presence of a co-reagent, such as triphenylphosphine, in a suitable solvent (e.g. THF, DCM and the like) and at an appropriate temperature. Scheme 22 X-OH Halogenation _ Sonogashira -L-z X-L1 Pd* X-L1 H N 12 N-Alkylation
X
Gq1 The resulting acetylenic halide may be submitted to substitution as described in Scheme 22 and according to the method illustrated in S.J. Pastine, S.W. Youn, D. Sames, Org. Left, 2003, 5, 1055-1058. The substitution reaction may be promoted by a nucleophile in the presence of a base such as K 2
CO
3 , Cs 2
CO
3 , NaH and the like in a suitable solvent (e.g. dimethylformamide, acetone, tetrahydrofuran), at an appropriate temperature. The resulting terminal alkyne is coupled to a substituted 5,6-heterocyclic containing nitrogen adjacent to the leaving group L 1 by Sonogashira procedure described in Scheme 3. In another embodiment of the present invention, depicted in Scheme 23, a suitable acetylenic halide bearing an appropriate protectiong group (e.g. trimethylsilyl and the like) may be reacted with a substituted 5-, 6-heterocyclic containing containing an N to produce' a N-alkylated heterocyclic derivative as illustrated in Scheme 22. The subsequent deprotection of the PG 1 according to methods known in the art, followed by Sonogashira coupling affords the compound of formula II-B.
WO 2005/123703 PCT/IB2005/002390 74 Scheme 23
X-L
1 N-Alkylation P PG 1 __ \ -9 Z lGq X-N9' HN-Z i2 Deprotection X--N 0Z 10 Sonogashira Z\ Pd. X-N, Z -L2 ei GqG The compounds of formula II-C wherein W, B', B 2 , B 3 and G3 are as described above and X is CH 2 -OC(=O) may be prepared according to the synthetic sequences illustrated in Scheme 24. Scheme 24 Sonogashira Esterification OH Pd* OH B 2 -BI OH 0 BI:B2 Gq 0 ~ The acetylenic alcohol is reacted with an appropriate substituted 5-, 6 heterocyclic containing containing an N adjacent to the leaving group L, under Sonogashira conditions to produce the substituted the heterocyclic acetylenic alcohol. In turn, the heterocyclic acetylenic alcohol may be converted to an ester derivative using the approach outlined in the Scheme 24. The reaction may be promoted by coupling agents known in the art of organic synthesis such as EDCI (1 (3-Dimethylaminopropy)-3-ethylcarbodiimide), DCC (N,N'-Dicyclohexyl carbodiimide), in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N dimethylformamide, dioxane). Typically, a co-catalyst such as DMAP (N,N-diimethyl aminopyridine) will also be present in the reaction mixture. The reaction typically proceeds at ambient temperature for a time in the range of about 4 up to 12 hours. Thus, in Scheme 24, LI may be a good leaving group capable of undergoing a Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonate and the like. In the Scheme 25, a compound of formula II-C wherein W, B 1 , B 2 , B3 and Gq are as described above and X is CH 2 -C(=O)-O may be prepared according to the synthetic sequences illustrated in Scheme 24. Scheme 25 Esterification OH B2-B0_OH OO B :B Sonogashira B -B o B 2 BI OH B B3('5L 0 \~ 3 Gqq WO 2005/123703 PCT/IB2005/002390 75 The compounds of formula 11-C wherein W and B', B 2 , B 3 , and Gq are as described above and X is CH 2 -NHC(=O) may be prepared according to the synthetic sequences illustrates in the Schemes 26-27. Scheme 26
B
2 rB 1 Coupling ,B 2
:B
1 Protecting group B2:B 0 B NH 2 + HO N B N G, NH GN PG 1 Gq Gq In turn, the pentynoic acid may be converted to aide derivative using the approach outlined in the Scheme 6. The reaction may be promoted by coupling agent known in the art of organic synthesis such as EDCI (1-(3-Dimethylaminopropyl)-3 ethylcarbodiimide), DCC (N,N'-Dicyclohexyl-carbodiimide), in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, NN-dimethylformamide, dioxane) Typically, a co-catalyst such as HOBT (Hydroxybenzotriazole) will also be present in the reaction mixture. The reaction typically proceeds at ambient temperature for a time in the range of about 4 up to 12 hours. N-protected derivative of the resulting amide may be prepared according to the method described in J.Med.Chem., 2000, 43, 3718-3735, by using for example
BOC
2 0 in a presence of DMAP in a suitable solvent such as DCM. The reaction typically proceeds at ambient temperature for a time in the range of about 4 up to 12 hours. Thus, in Scheme 26, PG includes carbamates such as EtO-C(=O), MeO C(=O), Ph-CH 2 -0-C(=O) or tBuOC(=O) and the like. Scheme 27 0 0 2:B1 OSonogashira B =B2
B
3 N- +W - N GPG PG Deprotection 0 W = HN B 3 The resulting acetylenic may be submitted to Sonogshira cross coupling as described in Scheme 27 according to the method outlined in the Scheme 3: Removal of the protecting group may be achieved under classical condition well known in the art, either under acidic conditions (HCl, H 2 S04, TFA and the like) or basic condition (NaOH, KOH, NH 3 and the like) in a suitable solvent such as THF, DCM or MeOH. Thus, in Scheme 27, L, may be a good leaving group capable of undergoing a Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonate and the like.
WO 2005/123703 PCT/IB2005/002390 76 The compounds of formula II-C wherein W and B', B 2 , B , and Gq are as described above and X is CH 2
-NR
9 C(=O)-Ci-C 6 -alkyl or CH2-NR9S(=O) 2
-C
1
-C
6 alkyl may be prepared according to the synthetic sequences illustrated in the Schemes 28-29. Scheme 28 Sonogashira Mesylation OH Pd* OH O L2
R
9
-NH
2 0'R9 In the Scheme 28, the acetylenic alcohol is reacted with an appropriate substituted 5-, 6-heterocyclic containing containing an N adjacent to the leaving group L1 to produce a substituted heterocyclic alcohol. The alcohol group is converted to a better leaving group by using an appropriate sulfonyl chloride (e.g. p toluenesulphonyl chloride or methansulfonyl chloride and the like) in a presense of a base (e.g. NEt 3 , DIEA) and in a suitable solvent (DCM, THF and the like). The reaction typically proceeds at ambient temperature for a time in the range of about 4 up to 12 hours. The intermediate sulfonate is converted into a N-Alkylated derivative by using an excess of appropriate amine in aqueous solution. The reaction takes place in a range of temperature between 30-50'C for 3h according to the method described in the J. Org. Chem.; Gao, Y.; Sharpless, K. B.; 53; 17; 1988; 4081-4084. Thus, in Scheme 28, LI may be a good leaving group capable of undergoing a Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonate and the like, L2 may be a good leaving group capable of undergoing nucleophilic substitution such as trifluoromethanesulfonate, mesylate or p-toluenesulfonate. Scheme 29 0B2 'RI '< R o N R9 R '0 Sulfonylation A 00 BI B 2 A 'IB 2 I!- Gq Gq In the Scheme 29, carboxylic acids (L1 is OH) or their more reactive derivatives (LI may be selected from Cl, Br, and the like) is reacted with an appropriate amine that produce amide according to Scheme 28. The acylation reaction may be promoted by coupling agents known in the art of organic synthesis such as WO 2005/123703 PCT/IB2005/002390 77 EDCI (1-(3-Dinethylaminopropyl)-3-ethylcarbodiimide), DCC (NN'-Dicyclohexyl carbodiimide) or by polymer-supported coupling agents such as polymer-supported carbodiimide (PS-DCC, ex Argonaut Technologies), in the presence of a suitable base such as triethylamine, diisopropyl-ethylamine, in a suitable solvent (e.g. tetrahydrofuran, dichloromethane, N,N-dimethylformamide, dioxane). Typically, a co-catalyst such as HOBT (1-Hydroxy-benzotriazole), HOAT (1-Hydroxy-7 azabenzotriazole) and the like may also be present in the reaction mixture. The reaction typically proceeds at ambient temperature for a time in the range of about 2 hours up to 12 hours. Similarly, sulfonyl chloride derivatives (LI is OH) may also reacted with amine derivatives according to the process described in the Scheme 29. The compounds of formula U-A wherein W, Z 9 , Z", Z' 2 , Z 13 , Z 14 , Z1 5 , Z 16 and Z are as described above and Z 10 is N may be prepared according to the synthetic sequences illustrated in Scheme 30. Scheme 30 OHSonogashira O +H-Z-iO OH Pd' OH Zj- 1 Z~6 Mitsunobu Z~o 1 15 z z, A substituted 5-, 6-heterocyclic containing a N adjacent to the leaving group Li is reacted with but-3-yn-l-ol in a manner similar to the procedure presented for Scheme 21. Thus, in Scheme 31, Li may be a good leaving group capable of undergoing a Sonogashira reaction such as Cl, Br, I or trifluoromethanesulfonate and the like. The resulting alcohol may be subsequently converted into a compound of formula H-A according to the method illustrated in M.S. Malamas, J. Sredy, I. Gunawan, B. Mihan, D.R. Sawicki, L. Seestaller, D. Sullivan, B.R. Flam, J: Med. Chem. 2000, 43, 995-1010. The Mitsunobu reaction may be promoted by a reagent such as diethylazodicarboxylate, di-tert-butylazodicarboxylate and the like in the presence of triphenyphosphine, in a suitable solvent (e.g. dichloromethane), at an appropriate temperature. In another embodiment of the present invention, compounds of formula [-Al wherein W, B', B 2 , B 3 and Gq are as described above may be prepared, as depicted in Scheme 31, from the methyl imidate according to the method illustrated in M.M. Ponpipom, R.L. Bugianesi, J.C. Robbins, T.W. Doebber, T.Y. Shen, J. Med. Chem. 1981, 24, 1388-1395. The subsequent cyclization may be promoted under mild conditions and followed by Sonogashira coupling.
WO 2005/123703 PCT/IB2005/002390 78 Scheme 31 CN Na NH HB 3 B- Cyclization MeOH OMe H 2 N B
B
3
B
1 Sonogashira W ~~-~ -G N B'j N- Bi The compounds of formula II-Al wherein W, B 1 , B 2 , B 3 and Gq are as described above may be prepared according to the following synthetic sequences describe in Scheme 32. Scheme 32 H HH BG cyclization: L 1 + -B G OH H 2 N B 2 ) N, B 2 Sonogashira 3 -G N ,B 2 ) Pentynoic acid is reacted with an aryl- or heteroaryl-amine where B 3 0 or S, in the presence of a mixture of triphenylphosphine and CC1 4 , in an appropriate solvent, in the presence o a base, followed by Sonogashira coupling as described in Scheme 3, in order to lead to benzoxazole or benzothiazole compounds. The compounds of formula II-Al wherein W, B', B 2 , G4 are as described above and B 3 = C=C or N=C may be prepared according to the following synthetic sequences illustrated in Scheme 33. Scheme 33 B3 B1 Base MeSi - + \ B -Gq Me 3 Si B3 B G4 X N B 2 ) N Gqi N B 2 Base or F -GI Sonogashira L + B G W G G N: B 2 N B 2 3i An appropriate 2-methyl-heteroalkyl is coupled to (3-X-prop-1-ynyl) trimethyl-silane derivative wherein X is a good leaving group such as Cl or Br and the like, in the presence of a strong base such as n-butyllithium, lithium diisopropylamine and the like. Trimethylsilyl group is removed under basic condition (e.g. NaOH, KOH, K 2 C0 3 ) or in the presence of fluoride ions (N-tetrabutylammonium fluoride WO 2005/123703 PCT/IB2005/002390 79 and the like). The resulting terminal alkyne is coupled to a substituted 5,6 heterocyclic containing nitrogen adjacent to the leaving group L 1 by Sonogashira procedure described in Scheme 3. The compounds of formula II-A3-a wherein R', R 2 , R 3 , R 4 and Gq are as described above and B'=C and X=CH 2 may be prepared according to the following synthetic sequences illustrated in Scheme 34. Scheme 34 MeSs NH2+ -Ga Mi~-G4 P(OEt)3 MeSs N G Me~I MeSl i ~q- N TG EHE NH2, N 0 Base or F R' R 1 2 Sonogashira R+ -- G R4NNR 4 N L, Trimethylsilanyl-but-3-ynylamine is reacted with substituted 1,2 nitrobenzaldehyde in an appropriate solvent such as toluene, ethanol... The resulting imine is reacted in the presence of triethylphosphite at a certain temperature in order to lead to substituted indazoles as in the method illustrated in T.J. Schwan, L.J. Honkomp, C.S. Davis, G.S. Lougheed, J. of Pharm. Sciences 1978, 7, 1022-1024. Trimethylsilyl group is removed under basic condition (e.g. NaOH, KOH, K 2 C0 3 ) or in the presence of fluoride ions (N-tetrabutylammonium fluoride and the like). The resulting terminal alkyne is coupled to a substituted pyridine having a leaving group
L
1 by Sonogashira procedure described in Scheme 3. The compounds of formula II-A3-a2 wherein R', R2, R3, R4 and Gq are as described above may be prepared according to the following synthetic sequences illustrated in Scheme 35. Scheme 35 NaNO 2 + AcidOH+ HN Gq Mitsunobu a'2+H 2 N- - NG H+H
R
2
R
2 R'
R
3
R
1 ,N - Gq Sonogashira / N G R3 N' -G+ 3 ,~ IN_: N, -Gq
R
4 N LI NR4 Benzotriazoles are prepared from substituted benzene-1,2-diamine in the presence of sodium nitrite and acetic acid as in the method illustrated in J. A. Montgomery, K. Hewson, J. Med. Chem. 1965, 8, 737-740. Then but-3-yn-1-ol is reacted with benzotriazoles through Mitsunobu reaction which may be promoted by diethylazodicarboxylate, di-tert-butylazodicarboxylate and the like in the presence of triphenyphosphine, in a suitable solvent (e.g. tetrahydrofuran), at an appropriate WO 2005/123703 PCT/IB2005/002390 80 temperature. The resulting terminal alkyne is coupled to a substituted pyridine via Sonogashira procedure described in Scheme 3. The compounds of formula II-B1 wherein W and Gq are as described above and X=CH 2 and B '=C may be prepared according to the synthetic sequences illustrated in Scheme 36. Scheme 36 - HG 1 OH 00 0 HO G'G 1 Oxidation G' +HN HN CI H 2 N G 2
G
2 G Cyclization L+O G , Sonogashira o G W Ll + ~ I NCG2 NX G 2 An acid chloride is reacted with an aminoalcohol under basic conditions such as triethylamine in a suitable solvent (e.g. DCM). The resulting amidoalcohol is oxidized in the presence of PCC followed by cyclization with POC1 3 and Sonogashira coupling as described in Scheme 3. The compounds of formula II-C wherein W, X, B', B 2 , B 3 and Gq are as described above may be prepared according to the synthetic sequences illustrate in Scheme 37. Scheme 37 L1 M Substitution L1 + Sonogashira MgBr G q 3 Gq Gq Propargylation may be promoted by an aryl- or heteroaryl-alkyl halide and propargylmagnesium bromide in the presence of an appropriate solvent (e.g. tetrahydrofuran) at an appropriate temperature, followed by Sonogashira coupling as described in Scheme 3. Pharmacology Some of the compounds of Formula I have been tested according to the following methods. mGluR5 binding assay Activity of compounds of the invention was examined following a radioligand binding technique using whole rat brain and tritiated 2-methyl-6-(phenylethynyl) pyridine ( [ 3 HJ-MPEP) as a ligand following similar methods than those described in F. Gasparini et al. Bioorg. Med. Chem. Lett. 2002, 12, 407-409 and in J. F. Anderson et al. J. Pharmacol. Exp. Ther. 2002, 303, 3, 1044-1051.
WO 2005/123703 PCT/IB2005/002390 81 Membrane preparation: Cortices were dissected out from brains of 200-300g Sprague-Dawley rats (Charles River Laboratories, L'Arbresle, France). Tissues were homogenized in 10 volumes (vol/wt) of ice-cold 50 mM Hepes-NaOH (pH 7.4) using a Polytron disrupter (Kinematica AG, Luzern, Switzerland) and centrifuged for 30 min at 40,000 g. (4'C). The supernatant was discarded and the pellet washed twice by resuspension in 10 volumes 50 mM HEPES-NaOH. Membranes were then collected by centrifugation and washed before final resuspension in 10 volumes of 20 mM HEPES-NaOH, pH 7.4. Protein concentration was determined by the Bradford method (Bio-Rad protein assay, Reinach, Switzerland) with bovine serum albumin as standard. 0 [ 3 H]-MIPEP binding experiments: Membranes were thawed and resuspended in binding buffer containing 20 mM HEPES-NaOH, 3 mM MgC1 2 , 3 mM CaC1 2 , 100 mM NaCl, pH 7.4. Competition studies were carried out by incubating for 1h at 4'C: 3 nM [ 3 H]-MPEP (39 Ci/mmol, Tocris, Cookson Ltd, Bristol, U.K.), 50 gg membrane and a concentration range of 0.003 nM- 30 pM of compounds, for a total reaction volume of 300 [1. The non specific binding was defined using 30 ptM MPEP. Reaction was terminated by rapid filtration over glass-fiber filter plates (Unifilter 96-well GF/B filter plates, Perkin Elmer, Schwerzenbach, Switzerland) using 4 x 400 pl ice cold buffer using cell harvester (Filternate, Perkin-Elmer, Downers Grove, USA). Radioactivity was determined by liquid scintillation spectrometry using a 96-well plate reader (TopCount, Perkin-Elmer, Downers Grove, USA). * Data analysis: The inhibition curves were generated using the Prism GraphPad program (Graph Pad Software Inc, San Diego, USA). IC 50 determinations were made from data obtained from 8 point-concentration response curves using a non linear regression analysis. The table below represents the mean of IC 50 obtained from at least three independent experiments of selected molecules performed in duplicate.
WO 2005/123703 PCT/IB2005/002390 82 Example N ICSG (nM) Example N* IC, 0 (nM) Example-N IC<o (nM) Example N* IC 50 (nM) Example N* ICso (nM) 1 <500 51 <10 000 98 < 10 000 148 <10 000 204 <10 000 2 <10000 52 <10000 99 <10000 149 <50 205 <10000 3 <10 000 53 <10 000 100 <10 000 150 <50 206 <10 000 4 <10000 54 <10000 101 <50 151 <50 207 <10000 5 <10 000 55 <10 000 102 <10 000 152 <50 208 <500 7 <500 56 <10000 103 <50 153 <10000 209 <50 8 <50 57 <10000 104 <50 154 <10000 211 <10000 9 <10000 58 <10000 105 <50 155 <50 212 <10000 10 <10 000 59 <10 00D 107 < 500 156 <50 213 <10 000 12 <10000 60 <10000 108 <500 157 <10000 215 <10000 13 <500 61 <10 000 109 < 500 159 <10 000 216 <10 000 14 <10000 62 <50 111 <10000 160 <10000 217 <10000 15 <500 63 <50 112 <50 161 <10 000 218 <500 16 <10000 64 <50 113 <10000 163 <50 219 <10000 17 <10000 65 <50 114 <50 164 <50 220 <10000 18 <10000 66 <500 116 <50 165 <50 221 <10000 19 <10000 67 <10000 117 <10000 166 <500 222 <10000 20 <10000 68 <10000 118 <500 167 <500 223 <500 21 <10 000 69 <50 120 <10 000 168 <10 000 224 <50 22 <10000 70 <10000 121 <10000 169 <10000 225 <50 23 <10000 71 <10000 122 <10000 170 <100.00 226 <10000 24 <10 000 72 <10 000 123 <10 000 171 <10 000 227 <10 000 25 <500 73 <10 000 124 < 10 000 172 <10 000 228 <50 26 <10 000 74 <10 000 125 <10 000 174 <10 000 230 <10 000 28 <10000 75 <10000 126 <50 175 <10000 231 <10000 29 <10 000 76 <10 000 127 <10 000 176 <10 000 232 <10 000 30 <10 000 77 <50 128 < 50 177 <10 000 233 <10 000 31 <50 78 <10 000 129 < 50 178 <10 000 234 <10 000 32 <10000 79 <10000 130 <50 179 <500 235 <50 33 <50 80 <50 131 <50 180 <10000 236 <50 34 <1000 81 <50 132 <50 181 <10000 241 <50 35 <50 82 <50 133 <10 000 182 <0 000 242 <10 000 36 <10000 83 <10000 134 <10000 183 <500 243 <10000 37 <10000 84 <10000 135 <10000 186 <10000 244 <10000 38 <10000 86 <50 136 <10000 187 <10000 245 <10000 40 <10000 87 <10000 137 <50 188 <10000 246 <10000 41 <10000 88 <50 138 <10000 189 <10000 247 <10000 42 <10 000 89 <50 139 <50 190 <500 249 <10 000 43 <10000 90 <50 140 <10000 191 <10000 25 <50 44 <10000 91 <50 141 <50 192 <500 256 <50 45 <10000 92 <50 142 <10000 193 <500 46 <10000 93 <50 143 <10000 194 <10000 47 <10000 94 <50 144 <10000 197 <10000 48 <500 95 <10000 145 <50 198 <10000 49 <10000 96 <50 146 <50 200 <10000 50 <10000 97 <10000 147 <50 202 <10000 WO 2005/123703 PCT/IB2005/002390 83 The compounds of the present invention present a high affinity for mGluR5 receptor. As allosteric modulators, they are useful for the production of medications, especially for the prevention or treatment of central nervous system disorders as well as other disorders modulated by this receptor. The compounds of the invention can be administered either alone, or in combination with other pharmaceutical agents effective in the treatment of conditions mentioned above. Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the thus described invention may be varied in many ways by those skilled in the art. The following non-limiting examples are intending to illustrate the invention. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds. Marble Burying model of anxiety Anxiety models in rodents are used as standard tests to demonstrate anxiolytic-like properties of novel compounds. Mice exhibit a tendency to bury harmless novel objects when encountered in a test cage. Marble burying behavior in mice is reduced by compounds which are efficacious anxiolytics in humans. Thus, marble burying in mice has been used as a model for the prediction of anxiolytic-like effects of compounds (Millan, M.J. et al., Neuropharmacology, 42:677-684 (2002)). Selective negative allosteric modulators (allosteric antagonists) of the metabotropic glutamate receptor subtype 5 (mGluR5) have been shown previously to reduce marble burying in mice (Spooren, W.P. et al., Journal of Pharmacology and Experimental Therapeutics, 295:1267-1275 (2000)). These results demonstrate that the marble burying test is a useful model for demonstrating the anxiolytic potential of compounds which are antagonists of mGluR5. Such compounds may be useful in the treatment of anxiety and related disorders. Subjects: The present studies were performed in accordance with the animal care and use policies of Addex Pharmaceuticals and the EEC directives on the protection of animals used for experimental and other scientific purposes (86/609/EEC and subsequent revisions). Male C57BL6/j mice (20-30 g) 7 weeks of age at the time of delivery were group housed in a temperature and humidity controlled facility on a 12 hour light /dark cycle for at least 5 days before use. Mice had access to food and water ad libitum except during marble burying experiments. Assessment of marble burying: The effect of compounds on marble burying in mice was tested. On the day of the test, animals were marked on their tails and weighed in a separate preparation room 1 hour before drug administration. Test compound or vehicle was administered po 60 minutes prior to the test session. Marble burying was tested in a separate experimental room. For the test, mice were placed individually into clear plastic cages (16 x 22 x 14 cm) with 5 cm of sawdust and 10 marbles evenly WO 2005/123703 PCT/IB2005/002390 84 spaced against the walls of the cage. The mice were left undisturbed in the cages for 30 minutes. After removal of the mice from the test cages, the number of marbles buried was counted. A marble was considered buried if it was 2/3 or more covered. Compound administration: Test compounds were dissolved in a solution of 80% 0.1N hydrochloric acid and 20% Tween 80 and adjusted to pH 6 with 1M NaHCO3. Test compounds were administered by oral gavage (po) in a volume of 10 ml/kg. Compound-vehicle-treated mice received the equivalent volume of vehicle solution po in the absence of added compound. Statistical analyses: Statistical analyses were performed using GraphPad PRISM version 4.01 statistical software (GraphPad, San Diego, CA, USA). Data were analyzed using one-way analysis of variance (ANOVA) followed by Bonferroni corrected multiple comparisons, or t tests if only 2 groups were present. The significance level was set at p<0.05. Effect of compounds on marble burying in mice The effect of Example 256 on marble burying in mice is shown in Figure 1. As can be seen in the figure, Example 256 significantly attenuated marble burying in mice (f (3,36) = 5.04, n = 10/group). Bonferroni-corrected multiple comparisons revealed a statistically significant difference showing that mice treated with 30 mg/kg po of Example 256 buried fewer marbles than vehicle-treated mice (t = 3.686, p < 0.01). These results demonstrate that Example 256 attenuates marble burying in mice and suggests that compounds of Formula II-A2-a2 may be useful in the treatment of anxiety. The effect of Example 255 on marble burying in mice is shown in Figure 2. As can be seen in the figure, mice treated with 50 mg/kg po of Example 255 buried significantly fewer marbles than vehicle-treated mice (t (1, 18) = 3.92, n = 10/group). These results demonstrate that Example 255 attenuates marble burying in mice and suggests that compounds of the invention may be useful in the treatment of anxiety. Vogel conflict drinking model of anxiety in rats Anxiety models in rodents are used as standard tests to demonstrate anxiolytic-like properties of novel compounds. The Vogel conflict drinking model involves the conflict between thirst and receiving mild shocks for drinking water (punished drinking). Water-deprived rats are placed in a chamber and are periodically shocked for drinking water. The shocks suppress drinking and anxiolytics reverse this shock induced suppression of drinking. The Vogel conflict drinking model was first proposed as a screening model for anxiolytics (Vogel, J.R. et al., Psychopharmacologia (Berl.), 21:1-7 (1971)) and is widely accepted as a robust model for testing the anxiolytic-like properties of compounds (Millan, M.J. and Brocco M., European Journal of Pharmacology, 463:67-96 (2003)). Selective negative allosteric modulators (allosteric antagonists) of the metabotropic glutamate receptor subtype 5 (mGluR5) have been shown to increase punished drinking in rats (Varty, G.B. et al., Psychopharmacology (Berl.) 179:207-217. (2005)). These results demonstrate that the Vogel conflict drinking test is a useful WO 2005/123703 PCT/IB2005/002390 85 model for demonstrating the anxiolytic potential of compounds which are antagonists of mGluR5. Such compounds may be useful in the treatment of anxiety and related disorders. Subjects: The present studies were performed in accordance with the animal care and use policies of Addex Pharmaceuticals and the EEC directives on the protection of animals used for experimental and other scientific purposes (86/609/EEC and subsequent revisions). Male Sprague-Dawley rats (350 g) 7-9 weeks of age at the time of testing were group housed in a temperature and humidity controlled facility on a 12 hour light /dark cycle for at least 5 days before use. Rats had access to food ad libitum except during Vogel conflict drinking model experiments. Rats had access to water ad libitum until 48 hours prior to the test session. Assessment of Vogel conflict drinking: The effect of compounds on drinking in the Vogel conflict drinking model in rats was tested. Test chambers are housed in sound attenuating boxes and each chamber contains a stainless steel drinking spout and a steel grid floor (MedAssociates, Georgia, Vermont, USA). Forty-eight hours prior to the test session, rats were habituated to the test chambers for 10 minutes. Water was removed from the rats immediately after the habituation session. Twenty-four hours before the test session, rats were again placed into the test chambers and allowed to drink for 4 minutes. Rats were then allowed 1 hour of access to water and then water was removed. On the test day, rats were brought to the test room at least 30 minutes before the test session. Rats were placed individually into the test chamber for a 5 minute session. Rats received a shock every 20th lick on the drinking spout. The number of punished drinks was counted automatically by the computer interface. The number of punished drinks was compared between treatment groups. An increase in the number of punished drinks in rats treated with a compound is interpreted as an anxiolytic-like effect. Compound administration: Test compounds (Examples 256 and 130) were dissolved either in a solution of 80% 0.1N hydrochloric acid, 20% Tween 80 and adjusted to pH 6 with 1M NaHCO 3 (Example 256) or a 7.5% Arabic gum/H 2 O solution (Example 130). Test compounds were administered by oral gavage (po) in a volume of 3 ml/kg. Compound-vehicle-treated rats received the equivalent volume of vehicle solution po in the absence of added compound. Statistical analyses: Statistical analyses were performed using GraphPad PRISM version 4.01 statistical software (GraphPad, San Diego, CA, USA). Data were analyzed using one-way analysis of variance (ANOVA) followed by Bonferroni multiple comparisons. The significance level was set at p<0.05. Effect of compounds on drinking in the Vogel conflict drinking model in rats The effect of Example 256 on punished drinking in the Vogel conflict drinking test is shown in Figure 3. As can be seen in the figure, Example 256 significantly increased punished drinking in rats (f (2,26) = 6.845, n = 9-10/group). Bonferroni-corrected multiple comparisons revealed a statistically significant difference showing that rats treated with 10 mg/kg po of Example 256 accepted significantly more shocks than vehicle-treated rats (t = 3.585, p < 0.01).
WO 2005/123703 PCT/IB2005/002390 86 Example 130 also induced an anxiolytic effect in the Vogel conflict drinking test (Figure 4). Specifically, rats that received 30 mg/kg of Example 130 took significantly more punished licks than vehicle injected controls (t(1, 17) = 2.593, n = 9-10/group). These data indicate that Example 256 and 130 are anxiolytic in the Vogel conflict drinking test. Summary of behavioral results The results presented above demonstrate that Examples 255, 256, and 130 are effective in specific models of anxiety in rodents. These results suggest that compounds of the invention may be useful in the treatment of anxiety disorders and related disorders and diseases of the central nervous system. EXAMPLES Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification. % (percent) M (molar) AcOEt (ethyl acetate) mbar (millibar)
(BOC)
2 0 (Di-tert-butyl dicarbonate) MeOH (methanol) n-BuLi (n-butyllithium) mg (milligrams) 'C (Celsius degrees) MgSO 4 (magnesium sulphate) CDC1 3 (deuterated chloroform) MHz (megahertz) CHC1 3 (chloroform) min (minutes) Cul (copper iodide) pL(microliters) DAST (diethylaminosulfur trifluoride) mL (milliliters) DCM (dichloromethane) mmol (millimoles) dec. (decomposition) Mp (melting point) DIEA (diisopropyl ethyl amine) N (normal) DMAP (N,N-dimethylaminopyridine) N 2 (nitrogen) DMF (dimethylformamide) NaCI (Sodium chloride) DMSO (dimethyl sulfoxide) NaHCO 3 (sodium hydrogenocarbonate) EDCI.HCl (1-3(Dimethylaminopropyl)-3- NaOH (sodium hydroxide) ethylcarbodiimide, hydrochloride) Et 2 O (diethyl ether) Na 2
SO
4 (sodium sulphate) g (grams) N 4 C1 (ammonium chloride) h (hour) NI40H (ammonium hydroxide) 'H (proton) NMR (Nuclear Magnetic Reasonance) HCl (hydrochloric acid) PdC1 2 (PPh 3
)
2 (Bis(triphenylphosphine) palladium (II) dichloride HOBT (1-hydroxybenzotriazole) Pd(PPh 3
)
4 (tetrakis(triphenylphosphine)palladium(0) HPLC (High Pressure Liquid Chromatography) P 2 0 5 (phosphorus pentoxide) H2S04 (Sulfuric acid) POC1 3 (phosphorus oxychloride) Hz (Hertz) r.t. (room temperature)
K
2 C0 3 (potassium carbonate) THF (tetrahydrofuran) KI (potassium iodide) TLC (tin chromatography layer) LCMS (Liquid Chromatography Mass Spectrum) RT (Retention Time) LiA1H4 (lithium aluminium hydride) WO 2005/123703 PCT/IB2005/002390 87 All references to brine refer to a saturated aqueous solution of NaC1. Unless otherwise indicated, all temperatures are expressed in 'C (degrees Centigrade). All reactions are conducted not under an inert atmosphere at room temperature unless otherwise noted. The microwave oven used is an apparatus from Biotage (Optimizer m ) equipped with an internal probe that monitors reaction temperature and pressure, and maintains the desired temperature by computer control. 1 H NMR spectra were recorded on a Brucker 500MHz. Chemical shifts are expressed in parts of million (ppm, 5 units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s singletet, d (doublet), t (triplet), q (quadruplet), quint (quintuplet), m (multiplet). LCMS were recorded on a Waters Micromass ZQ 2996 system by the following conditions. Column 3.0*50mm stainless steel packed with 5gm XTerra RP C- 18; flow rate lml/min; mobile phase: A phase = 0.1% formic acid in water, B phase = 0.07% formic acid in acetonitrile. 0-0.5min (A: 95%, B: 5%), 0.5-6.0min (A: 0%, B: 100%), 6.0-6.5min (A: 95%, B: 5%), 6.5-7min (A: 95%, B: 5%); UV detection Diode Array:200-400nm; Injection volume: 3p tl. All mass spectra were taken under electrospray ionisation (ESI) methods. Most of the reaction were monitored by thin-layer chromatography on 0.25mm Macherey-Nagel silica gel plates (60F-2254), visualized with UV light. Flash column chromatography was performed on silica gel (220-440 mesh, Fluka). Melting point determination was performed on a Buchi B-540 apparatus. Example 1 2-Methyl-(4-(4-phenyl)but- 1 -vny1)thiazole To a solution of Cul (45 mg, 24 jimol) in triethylamine (3 mL) were added 4-bromo 2-methylthiazole (85 mg, 0.48 mmol) and (PPh 3
)
2 PdC1 2 (17 mg, 24 pmol). The reaction mixture was cooled to 0 0 C and 1-(but-3-ynyl)benzene (67 pl, 0.48 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated under reflux for 3 days. Triethylamine was evaporated, water was added and the aqueous phase was extracted twice with DCM. The organic phase was washed with NH 4 0H solution, dried over Na 2 S04, filtered and concentrated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 25 mg (0.1 mmol, 23%) of 2-methyl-(4-(4-phenyl)but-1-ynyl)thiazole as a yellow oil. LCMS (RT) : 4.87min; MS (ES+) gave m/z: 229.2. Example 2 2-(4-(3-(2-Ethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-vnvl)pyridine 2(A) 3.-Chloro-N'-hydroxv-2-methylbenzamidine WO 2005/123703 PCT/IB2005/002390 88 According to the general protocol for anidoxime synthesis described in Example 15(A), the conversion of 2-ethylbenzonitrile (0.92 g, 7 mmol) afforded 1.12 g of 2 ethyl-N'-hydroxybenzamidine (Yield: 97%) as white powder (M.P. = 54-55'C). Rf (DCM/MeOH: 97/3) : 0.20 LCMS (RT) : 0.81min; MS (ES+) gave m/z: 165.0 2(B) 5-(But-3-ynyl)-3-(2-ethvlphenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 3-chloro-N'-hydroxy-2-methylbenzamidine (560 mg, 3.4 mmol) afforded 343 mg of 5-(but-3-ynyl)-3-(2-ethylphenyl)-1,2,4-oxadiazole (Yield: 44%) as yellow oil. Rf (DCM/M\4eOH : 99/1) : 0.75 LCMS (RT) : 4.86min; MS (ES+) not detected 2(C) 2-(4-(3-(2-Ethvlphenyl)-1,2,4-oxadiazol-5-Y1)but-1-vnvl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2-ethylphenyl)-1,2,4-oxadiazole (342 mg, 1.51 mmol) afforded 213 mg of 2-(4-(3-(2-ethylphenyl)-1,2,4-oxadiazol-5-yl)but-1 ynyl) pyridine (Yield 46%) as yellow oil. LCMS (RT) : 4.71min; MS (ES+) gave m/z: 304.0 'NMR (CDC1 3 ), 6 (ppm) : 8.62 (s, H), 7.92 (d, H), 7.63 (t, H), 7.45-7.20 (in, 5H), 3.33 (t, 2H), 3.07 (t, 2H), 3.00 (q, 2H), 1.23 (t, 3H). Example 3 2-(4-(Pyridin-2-V1)but-3-ynyllisoindoline-1,3-dione 3(A) 4-(Pyridin-2-y1)but-3-yn-1-oI The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (10.3 g, 65.1 mmol) and but-3-yn-l-ol (5.08 mL, 67.1 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 3:7 to 1:9) to yield 6.10 g (41.4 immol, 64%) of 4 (pyridin-2-yl)but-3-yn- 1 -ol as a brown oil. 3(B) 2-(4-(Pyridin-2-yl)but-3-yny1)isoindoline-1,3-dione 4-(Pyridin-2-yl)but-3-yn-1-ol (96 mg, 0.65 mmol), isoindoline-1,3-dione (140 mg, 0.97 mmol) and triphenylphosphine polymer bound 3 mmol/g (340 mg, 1.02 mmol) were dissolved in DCM (2 mL) and cooled to 0 0 C. Di-tert-butylazodicarboxylate (226 mg, 0.96 mmol) dissolved in DCM (0.5 mL) was added dropwise over 30 min. to the reaction mixture followed by THF (0.5 mL) and the reaction mixture was stirred for 16 h at room temperature. After filtration through celite, the organic phase was washed with a solution of NH 4 0H, brine, dried over Na 2
SO
4 , filtered and concentrated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:7) to yield 130 mg (0.47 mmol, 73%) of 2-(4-(pyridin-2 yl)but-3-ynyl)isoindoline-1,3-dione as an orange solid. LCMS (RT) : 3.08min; MS (ES+) gave m/z : 277.2. 'H-NMR (CDCl 3 ), 6 (ppm) : 2.91 (t, J=7.0, 2H), 4.02 (t, J=7.0, 2H), 7.34-7.43 (m, 1H), 7.47-7.55 (m, 1H), 7.73 (dd, J=3.0 and 5.5, 2H), 7.80-7.85 (m, 1H), 7.86 (dd, J=3.0 and 5.5, 2H), 8.56-8.61 (m, 1H).
WO 2005/123703 PCT/IB2005/002390 89 Example 4 2-(4-(Pyridin-2-yl)but-3-ynyl)phthalazin-1 (2H)-one The title compound was prepared in accordance with the general method of Example 3(B), from 4-(pyridin-2-yl)but-3-yn-1-ol (102 mg, 0.69 mmol, Example 3(A)) and phthalazin-1(2N)-one (152 mg, 1.04 mmol). The crude residue was pui4fied by flash chromatography (DCM/MeOH 99:1 to 97:3) followed by bulb-to-bulb distillation (100-C, 0.1 mbar) to yield 22 mg (79 mmol, 11%) of 2-(4-(pyridin-2-yl)but-3 ynyl)phthalazin- 1(2H)-one as a brown solid. LCMS (RT) : 2.70min; MS (ES+) gave m/z : 276.2. 'H-NMNIR (CDC1 3 ), 5 (ppm) : 3.18 (t, J=7.0, 2H), 4.59 (t, J=7.0, 2H), 7.72-7.85 (5H), 8.23 (s, 1H), 8.23-8.28 (m, 1H), 8.43 (d, J=7.5, 1H), 8.72 (d, J=6.0, 1H). Example 5 2-(4-Phenylbut-1-ynyl)quinoline The title compound was prepared in accordance with the general method of Example 1, from 2-chloroquinoline (300 mg, 1.83 mmol) and 1-(but-3-ynyl)benzene (200 mg, 1.54 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 148 mg (0.57 mmol, 37%) of 2-(4-phenylbut-l ynyl)quinoline as an orange oil. LCMS (RT) : 4.5 lmin; MS (ES+) gave m/z : 258.2. lH-NMR (CDC1 3 ), S (ppm) : 2.80 (t, J=7.5, 2H), 3.02 (t, J=7.5, 2H), 7.21-7.25 (in, 1H), 7.27-7.35 (4H), 7.43 (d, J=8.5, 1H), 7.52-7.56 (m, 1H), 7.70-7.74 (m, 1H), 7.79 (d, J=8.0, 1H), 8.09-8.20 (2H). Example 6 2-(4-Phenylbut-l-yny1)pyrimidine The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyrimidine (290 mg, 1.82 mmol) and 1-(but-3-ynyl)benzene (200 mg, 1.54 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 275 mg (1.32 mmol, 86%) of 2-(4-phenylbut-l ynyl)pyrimidine as a yellow oil. LCMS (RT) : 3.51min; MS (ES+) gave m/z : 209.2. 'H-NMR (CDCl 3 ), 5 (ppm) : 2.76 (t, J=7.5, 2H), 3.00 (t, J=7.5, 2H), 7.20-7.24 (2H), 7.25-7.28 (2H), 7.29-733 (2H), 8.70 (d, J=5.0, 2H).
WO 2005/123703 PCT/IB2005/002390 90 Example 7 2-(4-Phenylbut-1-yny1)benzoldloxazole To a solution of CuI (15 mg, 81 iLmol) in triethylamine (3 mL) were added 2 chlorobenzo[d]oxazole (250 ng, 1.63 mmol), (PPh 3
)
2 PdC 2 (57 mg, 81 ptmol), triphenylphosphine polymer bound 3 mmol/g (98 mg, 293 prmol) and a solution of 1 (but-3-ynyl)benzene (250 mg, 1.92 mmol) in DMF (0.5 mL). The reaction mixture was stirred for 25 min. at 120'C in the microwave cavity. The reaction was quenched as described in Example 1. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 163 mg (0.66 mmol, 40%) of 2-(4-phenylbut-1 ynyl)benzo[d]oxazole as an orange oil. LCMS (RT) : 4.84min; MS (ES+) gave m/z: 248.1. 'H-NMR (CDCl 3 ), 5 (ppm) : 2.81 (d, J=7.5, 2H), 3.00 (d, J=7.5, 2H), 7.21-7.26 (m, 1H), 7.26-7.29 (2H), 7.31-7.40 (4H), 7.48-7.51 (m, 1H), 7.70-7.72 (m, 1H). Example 8 2-(4-(Pyridin-2-yl)but-3-ynyl)benzordloxazole hydrochoride 8(A) 2-(But-3-yny1)benzo[dloxazole A solution of triphenylphosphine (16.0 g, 61.2 mmol) in a mixture of acetonitrile/pyridine 1:1 (30 mL) was added dropwise over 2 hours to a solution of pent-4-ynoic acid (2.00 g, 20.4 mmol), 2-aminophenol (2.31 g, 21.0 mmol), Et 3 N (8.50 mL, 61.2 mmol) and CC14 (7.87 mL, 81.6 mmol) in acetonitrile/pyridine 1:1 (20 mL). The reaction mixture was stirred for 2 days at room temperature and the solvent was evaporated. The residue was dissolved in DCM and washed with a saturated solution of NH40H. The aqueous phase was extracted twice with DCM. The resulting organic phase was dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 1.37 g (8.03 mmol, 39%) of 2-(but-3-ynyl)benzo[d]oxazole as a red oil. 8(B) 2-(4-(Pyridin-2-ylbut-3-ynyl)benzofdloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (746 mg, 4.67 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (800 mg, 4.67 mmol). Reaction time: 3 hours. The crude residue was dissolved in DCM, syn-2-pyridinecarboxaldoxime (684 mg, 5.60 mmol) was added and the reaction mixture was stirred overnight. The solvent was evaporated and the resulting crude product was purified by flash chromatography (DCM/MeOH 99:1) to yield 923 mg (3.72 mmol, 79%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid. 8(C) 2-(4-(Pyridin-2-yl)but-3-ynyllbenzordloxazole hydrochloride A solution of HC1 in dioxane (4.65 mL, 0.8 M, 3.72 mmol) was added to a solution of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole (923 mg, 3.72 mmol) in dioxane (50 mL). The resulting suspension was cooled at OC for 1 hour and was filtered. The precipitate was washed twice with dioxane and dried under vacuum to yield 2-(4 (pyridin-2-yl)but-3-ynyl)benzo[d]oxazole hydrochloride (830 mg, 2.91 mmol, 78%) as a white solid (M.P. = 143.5-145'C). LCMS (RT) : 3.29min; MS (ES+) gave m/z : 249.1.
WO 2005/123703 PCT/IB2005/002390 91 Rf (DCM/MeOH 98:2)= 0.1. 'H-NMR (CDCl 3 ), 6 (ppm) : 3.25 (t, J=7.4, 2H), 3.43 (t, J=7.4, 2H), 7.32-7.38 (2H), 7.52-7.56 (m, 1H), 7.69-7.73 (m, 1H), 7.74-7.80 (2H), 8.24-8.28 (m, 1H), 8.73 (d, J=6.0, 1H). Example 9 2-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pridine 9(A) Ethyl pent-4-ynoate In analogy to the method as described in Tetrahedron., 2000, 56, 5735-5742, a mixture of the 4-pentynoic acid (10 g, 102 mmol) and H 2 S0 4 98% (0.338 mL, 6.12 mmol) in ethanol (113 mL) was heated at 50'C overnight. The reaction mixture was concentrated and the crude product was dissolved in ethyl acetate, washed with NaHCO 3 1M and water. The solvent was removed under reduced pressure to afford 9.04 g of ethyl pent-4-ynoate (Yield : 70%) as a colorless oil. 9(B) Ethyl 5-(pyridin-2-yl)pent-4-ynoate In a dry reaction tube containing in suspension copper iodide (60 mg, 0.315 mmol) and triethylamine (17.70 mL, 126 mmol), were added 2-iodopyridine (1.29 g, 6.30 mmol) and the Pd(PPh 3
)
2 C1 2 (202mg, 0.315 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added ethyl pent-4 ynoate (790 mg, 6.30 nmol) in solution in 2 mL of triethylamine. Immediatly the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80'C for 20h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH 4 Cl, water and brine. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography system (prepacked silicagel column 25 g, DCM/MeOH : 98/2 as eluent) to afford 1.17 g of ethyl 5 (pyridin-2-yl)pent-4-ynoate (Yield: 78%) as brownish oil. 9(C) 5-(Pyridin-2-y1)pent-4-ynoic acid To a aqueous solution of 1M NaOH (9.9 mL) heated at 50'C, was added slowly a solution of ethyl 5-(pyridin-2-yl)pent-4-ynoate (2 g, 9.90 mmol) in 3 mL of ethanol. The reaction mixture was stirred 1h30 at 50'C and cooled to room temperature. An aqueous 1N HC1 (9.9 mL, 9.90 mmol) was then added and the solvent was removed under pressure to afford 2.3 g of 5-(pyridin-2-yl)pent-4-ynoic acid (Yield : 99%) as a brown solid which can be used without further purification. 9(D) 2-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-vnyl)pyridine A mixture of commercially available 4-fluoro-N'-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100'C for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water.The organic layer was dried over Na 2
SO
4 , filtred and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH : 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4 fluorophenyl)-1,2,4-oxadiazol-5-yl)but-l-ynyl)pyridine (Yield : 25%) as a yellow oil. LCMS (RT) : 3.99min; MS (ES+) gave m/z: 294.1 WO 2005/123703 PCT/IB2005/002390 92 'NMR (CDC1 3 ), a (ppm) : 8.64 (s, H), 8.10 (m, 2H), 7.68 (t, H), 7.41 (d, H), 7.27 (d, H), 7.21-7.14 (in, 2H), 3.32 (t, 2H), 3.07 (t, 2H). Example 10 2-(4-(3-Pheny)-1,2,4-oxadiazol-5-yl)but-1-ynvl)pyridine According to the protocol described in Example 9(D), the conversion of commercially available N'-hydroxybenzamidine (190 mg, 1.4 mmol) afforded 59 mg of 2-(4-(3 phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 15%) as yellow oil. LCMS (RT) : 3.83min; MS (ES+) gave m/z : 276.0 INMR (CDC1 3 ), 5 (ppm) : 8.64 (s, H), 8.09 (in, H), 7.70 (t, H), 7.54-7.46 (in, 3H), 7.42 (d, H), 7.30-7.25 (m, 2H), 3.33 (t, 2H), 3.09 (t, 2H). Example 11 2-Methyl-4-(4-ihenylbut-1-vnyl)-lH-imidazole 11(A) Ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate In general, modifications were made from the procedure given in J. Org. Chem., 1999, 64, 23, 8608-8615. A solution of commercially available 4-iodo-2-methyl-1H imidazole (520 mg, 2.5 mmol) in THF (8.3 mL), containing DIEA (1.07 mL, 6.25 miol) and DMAP (150 mg, 1.30 mmol), was cooled in a ice bath at 0CC. A solution of ethyl chloroformate (678 mg, 6.25 mmol) in THF (2.5 mL) was slowly added over a period of 20min to the reaction mixture. The reaction mixture was heated at 50'C for 48h and the solvent was removed under reduced pressure. The residue was dissolved in DCM and the organic layer was washed with brine, water, dried over MgSO 4 , filtered and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH : 97/3 as eluent) to afford 660 mg of ethyl 4-iodo-2 methyl-1H-imidazole-1-carboxylate (Yield : 94%) as a colorless oil. 11(B) Ethyl 2-methyl-4-(4-phenylbut-1-ynyl)-1H-inidazole-1-carboxylate In a dry reaction tube containing in suspension iodide copper (20 mg, 0.1 mmol) and triethylamine (5.81 mL, 41.40 mmol), were added ethyl 4-iodo-2-methyl-1H imidazole-1-carboxylate (580 mg, 2.07 mmol) and the Pd(PPh 3
)
2 Cl 2 (66 mg, 0.1 mnol). A yellow suspension is obtained and after a few minutes stirred at room temperature was added the commercially available 4-phenyl-1-butyn (269 mg, 2.07 mmol) in triethylamine (0.5 mL). Immediatly the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80'C for 20h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH 4 C1, water and brine, dried (MgSO 4 ) and concentrated. Purification by flash chromatography (prepacked 25 g silicagel column, DCM/MeOH : 99/1 as fluent) to afford 410 ig of ethyl 2-methyl-4 (4-phenylbut-1-yny)-1H-imidazole-1-carboxylate (Yield : 70%) as a brown oil. Rf (DCM/MeOH: 99/1) = 0.3 LCMS (RT) : 4.39min; MS (ES+) gave m/z: 283.1 11(C) 2-Methyl-4-(4-phenvlbut-1-ynyl)-1H-imidazole 0.45 mL of NaOH 2.0 N was added dropwise to a solution ethyl 2-methyl-4-(4 phenylbut-1-ynyl)-1H-imidazole-1-carboxylate (250 mg, 0.9 mmol) in ethanol (4.5 WO 2005/123703 PCT/IB2005/002390 93 mL) and the mixture was heated at 80'C overnight. Ethanol was concentrated under reduced pressure, To the crude producer was added water and the aqueous layer was extracted with DCM. The recombined organics layers were washed with brine, dried over MgS04, filtered and concentrated to afford 163 mg of 2-methyl-4-(4-phenylbut l-ynyl)-l-imidazole (Yield : 86%) as a beige solid (M.P. = 124-126'C). Rf (DCM/M\4eOH: 95/5) 0.3 LCMS (RT) : 0.64-2.41min; MS (ES+) gave m/z : 211.2 'NMR (CDC1 3 ), S (ppm) : 7.32-7.19 (m, 6H), 3.80 (s, NH), 2.89 (m, 2H), 2.67 (m 2H), 2.43 (s, 3H). Example 12 N-Methyl-N-phenyl-5-(pyridin-2-vl)pent-4-ynamide 12(A) N-methyl-N-phenvLpent-4-vnamide To a solution of N-methylbenzenamine (110 mg, 1.02 mmol) in DCM (3 mL) was successively added at R.T. 4-pentynoic acid (100 mg, 1.02 mmol), HOBT (171mg, 1.12 nmol) and EDCI.HCl (293 mg, 1.53 mmol). The reaction was stirred at R.T. overnight. The reaction was quenched with water. The organic layer was separated and washed with IM NaHCO 3 and water. The solvent was removed under reduced pressure to afford 150 mg N-nethyl-N-phenylpent-4-ynamide (Yield : 78%) as an orange oil which en be used without further purification. LCMS (RT) : 3.26min; MS (ES+) gave m/z: 188.1 12(B) N-Methyl-N-phenyl-5-(pyridin-2-yl)pent-4-vnamide According to the protocol described in Example 74(E), the conversion of N-methyl N-phenylpent-4-ynamide (150 mg, 0.80 mmol) afforded 130 mg of N-methyl-N phenyl-5-(pyridin-2-yl)pent-4-ynamide (Yield : 61%) as orange solid (M.P. = 68 71 C). Purification by flash chromatography (prepacked 25 g silicagel column, DCM/MeOH : 95/5 as eluent) Rf (DCM/MeOH: 95 /5) = 0.20 LCMS (RT) : 2.89min; MS (ES+) gave m/z : 265.1 'NMR (CDCl 3 ), 6 (ppm) : 8.55 (s, H), 7.73 (t, H), 7.48-7.40 (m, 3H), 7.36 (t, H), 7.29 (t, H), 7.25-7.20 (m, 2H), 3.30 (s, 3H), 2.77 (t, 2H), 2.45 (t, 2H). Example 13 N-(4-Fluorophenyll-N-methyl-5-(p6rdin-2-v1)pent-4-vnamide 13(A) N-(4-fluorophenyl)-N-methvlpent-4-ynamide According to the protocol described in Example 12(A), the conversion of 4-fluoro-N methylbenzenamine (127 mg, 0.52 mmol) afforded 180 mg of N-(4-fluorophenyl)-N methylpent-4-ynamide (Yield: 91%) as orange oil. LCMS (RT) : 3.38min; MS (ES+) gave m/z : 206.1 13(B) N-(4-Fluorophenv1)-N-methl-5-(pyridin-2-vl)pent-4-vnamide According to the protocol described in Example 74(E), the conversion of N-(4 fluorophenyl)-N-methylpent-4-ynamide (170 mg, 0.83 mmol) afforded 157 mg of N (4-fluorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide (Yield : 67%) as orange WO 2005/123703 PCT/IB2005/002390 94 oil. Purification by Flash chromatography (prepacked 25 g silicagel column, DCM/MeOH: 95/5 as fluent) Rf (DCM/MeOH: 95/5) = 0.23 LCMS (RT): 3.06min; MS (ES+) gave m/z: 283.1 'NMR (CDC1 3 ), 8 (ppm) : 8.55 (s, H), 7.65 (t, H), 7.47 (d, H), 7.24-7.18 (m, 3H), 7.15-7.08 (m, 2H), 3.26 (s, 3H), 2.75 (t, 2H), 2.41 (t, 2H). Example 14 2-(4-(2-Phenylthiazol-4-yl)but-l-ynyl)pyridine 14(A) 4-(Bromomethyl)-2-phenylthiazole Bromine (177 mg, 1.1 mmol) was added directly into a solution of triphenylphosphine (288 mg, 1.1 mmol) in DCM (2 mL) to give a kind of white precipitate. The temperature was cooled to -6'C. A solution of commercially available (2 phenylthiazol-4-yl)methanol (200 mg, 1.04 mmol) in DCM (1mL) was added dropwise. The resulting mixture was maintained at -6'C for 15min and then warmed to room temperature for 1h. A white precipitate was formed. The solution was filtered and the white precipitate was washed with DCM. The white precipitate was collected and dissolved in NaHCO 3 0.5M After 30min of stirring, the aqueous layer was extracted with DCM and the organic phase was washed with water, dried over MgS04, filtered and evaporated to afford 248 mg of 4-(bromomethyl)-2 phenylthiazole (Yield 71%) as a yellow oil. LCMS (RT) : 4.46min; MS (ES+): no ionisation 14(B) 4-(4-(Trimethylsilyl)but-3-yny1)-2-phenylthiazole According to the protocol described in Example 74(C), the conversion of 4 (bromomethyl)-2-phenylthiazole (185 mg, 0.73 mmol) afforded 191 mg of 4-(4 (trimethylsilyl)but-3-ynyl)-2-phenylthiazole (Yield: 92%) as yellow oil. LCMS (RT) : 5.56min; MS (ES+) gave m/z: 286.1 14(C) 4-(But-3-ynyl)-2-phenylthiazole According to the protocol described in Example 74(D), the conversion of 4-(4 (trimethylsilyl)but-3-ynyl)-2-phenylthiazole (191 mg, 0.67 mmol) afforded 111 mg of 4-(but-3-ynyl)-2-phenylthiazole (Yield: 77%) as yellow oil. LCMS (RT): 4.53min; MS (ES+) gave m/z: 214.1 14(D) 2-(4-(2-Phenylthiazol-4-yl)but-1-ynyl)pyridine According to the protocol described in Example 74(E), the conversion of 4-(but-3 ynyl)-2-phenylthiazole (111 Img, 0.52 mmol) afforded 88 mg of 2-(4-(2-phenylthiazol 4-yl)but-1-ynyl)pyridine (Yield : 58%) as brown oil. Purification by flash chromatography (prepacked 10 g silicagel column, DCM 100% as fluent). Rf (Cyclohexane/AcOEt: 60 /40) = 0.23 LCMS (RT) : 4.11min; MS (ES+) gave m/z : 291.1 'NMR (CDC1 3 ), ( (ppm) : 8.61 (s, H), 7.98-7.93 (m, 2H), 7.76 (t, H), 7.48-7.40 (m, 4H), 7.33 (n, H), 7.18 (m, H), 3.20 (t, 2H), 2.98 (t, 2H).
WO 2005/123703 PCT/IB2005/002390 95 Example 15 2-(4-(3-o-Toly)-1,2,4-oxadiazol-5-v1)but-1-ynyl)pyridine 15(A) N-Hydroxy-2-methylbenzamidine A mixture of 2-methyl-benzonitrile (0.950 mL, 8 mmol), hydroxylamine 50% in water (1.6 mL, 24 mmol) and EtOH (8 mL) was heated at 70'C for 48h. TLC analysis (DCM/MeOH : 97/3 as eluent) indicates the completion of the reaction. The solvent was removed under reduced pressure to afford 1.2 g of N'-hydroxy-2 methylbenzamidine (Yield : 100%) as a white powder (M.P. = 147-148.5 0 C).which can be used without further purification. Rf Amidoxime (DCM/MeOH : 97/3 as eluent) : 0.2 15(B) 5-(But-3-yny1)-3-o-tolyl-1,2,4-oxadiazole In a reactor tube, a mixture of N'-hydroxy-2-methylbenzamidine (555 mg, 3.7 mmol), 4-pentynoic acid (363 mg, 3.7 mmol), HOBT (0.56 g, 3.7 mmol) and EDCI.HCl (1.06 g, 5.55 mmol) in dioxane (7.4 mL) was stirred at R.T for 3h. After this time the mixture was heated at 80 0 C overnight in a reaction block. The mixture was concentrated. The organic layer was washed with water, NaOH 1N and water. The solvent was evaporated in a Genevac for 75min at 40'C using the low boiling point program. The crude product was purified by flash chromatography (Prepacked 10 g silicagel column) with DCM as eluent to afford 250 mg of 5-(but-3-ynyl)-3-o-tolyl 1,2,4-oxadiazole (Yield: 32%) as yellow oil. LCMS (RT) : 4.36min; MS (ES+) gave m/z: 213.1 Rf Oxadiazole (DCM/MeOH : 99/1 as eluent) : 0.75 15(C) 2-(4-(3-o-Tolvl)-1,2,4-oxadiazol-5-ylbut-1-vny1)pyridine In a dry reaction tube containing in suspension copper iodide (11 mg, 0.06 mmol) and triethylamine (3.3 mL, 24 mmol), were added 2-bromopyridine (115 pL, 1.2 mmol) and the Pd(PPh 3
)
2
C
2 (42 mg, 0.06 mmol) under N 2 . A yellow suspension is obtained and after 5 min of stirring at room temperature 5-(but-3-ynyl)-3-o-tolyl-1,2,4 oxadiazole (249 mg, 1.2 mmol) in solution in 0.7 mL of triethylamine was added under N 2 . Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80'C for 20h under N 2 . Triethylamine was concentrated under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with NH 4 C1, water, NaCl, dried (MgS04), and concentrated. The crude product was purified by flash chromatography (Prepacked 10 g silicagel column with DCM/MeOH : 99/1 as eluent) to afford 103 mg of 2-(4-(3-o tolyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 30%) as brown semi-solid. LCMS (RT) : 4.1 1min; MS (ES+) gave m/z : 290.1 1 H-NMR (CDC1 3 ), 6 (ppm) : 8.76 (s, H), 8.01 (m, H), 7.81 (m, H), 7.72 (m, H), 7.41 7.31 (m, 4H), 3.37 (m, 2H), 3.04 (m, 2H), 2.63 (s, 3H). Example 16 2-(4-(3-Benzyl-1,2.4-oxadiazol-5-vl)but-1-vnyl)pvridine 16(A) N'-Hydroxy-2-phenvlacetamidine WO 2005/123703 PCT/IB2005/002390 96 According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-phenylacetonitrile (0.93 mL, 8 mmol) afforded 1.2 g of N' hydroxy-2-phenylacetamidine (Yield: 100%) as beige powder (M.P. = 58-60 0 C). 16(B) 3-Benzyl-5-(but-3-yny1)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of N'-hydroxy-2-phenylacetamidine (555 mg, 3.7 mmol) afforded 165 mg of 3-benzyl-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield: 21%) as yellow oil. LCMS (RT) : 3.89min; MS (ES+) gave m/z : 213.1 16(C) 2-(4-(3-Benzyl-1,2,4-oxadiazol-5-yl)but-1-yny1)pyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 3-benzyl-5-(but-3-ynyl)-1,2,4-oxadiazole (165 mg, 0.8 mmol) afforded 22 mg of 2-(4-(3-benzyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 10%) as brown oil. LCMS (RT) : 3.61min; MS (ES+) gave nm/z : 290.1 'H-NMR (CDC1 3 ), 5 (ppm) : 8.76 (s, H), 7.72 (t, H), 7.35-7.24 (m, 7H), 4.08 (s, 2H), 3.22 (in, 2H), 2.95 (m, 2H). Example 17 2-(4-(3-(2-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 17(A) (2-(2-Fluoropheny1)-N'-hydroxyacetamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-(2-fluorophenyl)acetonitrile (1.03 mL, 8 mmol) afforded 1.33 g of 2-(2-fluorophenyl)-N'-hydroxyacetamidine (Yield : 99%) as white powder (M.P. = 85-87-C). 17(B) 3-(2-Fluorobenzyl)-5-(but-3-ynl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of 2-(2-fluorophenyl)-N'-hydroxyacetamidine (622 mg, 3.7 mmol) afforded 212 ing of 3-(2-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield :25%) as yellow oil. LCMS (RT) : 3.96min; MS (ES+) gave m/z : 231.1 17(C) 2-(4-(3-(2-Fluorobenzvl)-1,2,4-oxadiazol-5-yl)but-l-ynyl)pyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 3-(2-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (212 mg, 0.9 mmol) afforded 15 mg of 2-(4-(3-(2-fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1 ynyl)pyridine (Yield: 5%) as brown oil. LCMS (RT) : 3.63min; MS (ES+) gave m/z: 308.1 'IH-NMvIR (CDC1 3 ), 6 (ppm) : 8.76 (s, H), 7.85 (s, H), 7.70 (m, H), 7.33-7.22 (m, 3H), 7.12-7.04 (m, 2H), 4.13 (s, 2H), 3.26 (m, 2H), 3.01 (m, 2H).
WO 2005/123703 PCT/IB2005/002390 97 Example 18 2-(4-(3-(2-Methylbenzyl)-1,2,4-oxadiazol-5-Y1)but-1-ynv1)pyridine 18(A) N'-Hydroxy-2-o-tolylacetamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-o-tolylacetonitrile (1 mL, 8 mmol) afforded 1.3 g of N' hydroxy-2-o-tolylacetamidine (Yield: 99%) as white powder (M.P. 116-118'C). 18(B) 3-(2-Methylbenzyl)5-(but-3-vnv1)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of N'-hydroxy-2-o-tolylacetamidine (607 mg, 3.7 mmol) afforded 126 mg of 3-(2-methylbenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield: 15%) as yellow oil. LCMS (RT) : 4.16min; MS (ES+) gave m/z : 227.1 18(C) 2-(4-(3-(2-Methylbenzyl)-1,2,4-oxadiazol-5-yl)but-1-vnyl)pyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 3-(2-methylbenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (126 mg, 0.6 mmol) afforded 68 mg of 2-(4-(3-(2-methylbenzyl)-1,2,4-oxadiazol-5-yl)but I -ynyl)pyridine (Yield: 37%) as brown oil. LCMS (RT) : 3.84min; MS (ES+) gave m/z : 304 'H-NMR (CDCl 3 ), § (ppm) : 8.57 (d, H), 7.68 (t, H), 7.35 (t,H), 7.30-7.22 (m, 3H), 7.12-7.12 (m, 2H), 4.07 (s, 2H), 3.21 (t, 2H), 2.97 (t, 2H), 2.38 (s, 3H). Example 19 2-(4-(3-(4-Fluorobenzyl)-1.2,4-oxadiazol-5-yl)but-1-vny1)pvridine 19(A) 2-(4-Fluoropheny1)-N'-hydroxyacetamidine According to the general protocol for amidoxiime synthesis described in Example 15(A), the conversion of 2-(4-fluorophenyl)acetonitrile (0.97 mL, 8 mmol) afforded 1.34 g of 2-(4-fluorophenyl)-N'-hydroxyacetainidine (Yield: 100%) as white powder (M.P. = 104-106-C). 19(B) 3-(4-Fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of 2-(4-fluorophenyl)-N'-hydroxyacetamidine (622 mg, 3.7 mmol) afforded 388 mg of 3-(4-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield : 46%) as yellow oil. LCMS (RT) : 4.01min; MS (ES+) gave m/z : 231.1 19(C) 2-(4-(3-(4-Fluorobenzvl)-1,2,4-oxadiazol-5-Y)but-1-vnyvlpyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 3-(4-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (388 mg, 1.7 mmol) afforded 80 mg of 2-(4-(3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-l ynyl)pyridine (Yield: 15%) as brown oil. LCMS (RT) : 3.71min; MS (ES+) gave m/z : 308.1 1H-NMR (CDC1 3 ), 6 (ppm) : 8.57 (s, H), 7.80 (s, H), 7.33-7.28 (m, 4H), 7.02-6.96 (m, 211), 4.05 (s, 2H), 3.26 (in, 2H), 2.96 (m, 2H).
WO 2005/123703 PCT/IB2005/002390 98 Example 20 2-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-vl)but-1-vnvl)pyridine 20(A) N'-Hydroxy-2-(4-methoxyphenv1)acetamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-(4-methoxyphenyl)acetonitrile (1.09 mL, 8 mnol)afforded 1.43 g of N'-hydroxy-2-(4-methoxyphenyl)acetamidine (Yield : 99%) as white powder (M.P. = 104-106'C). 20(B) 3-(4-Methoxvbenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of N'-hydroxy-2-(4-methoxyphenyl)acetamidine (666 mg, 3.7 mmol) afforded 211 mg of 3-(4-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield : 24%) as yellow oil. LCMS (RT) : 3.89min; MS (ES+) gave m/z: 243.1 20(C) 2-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but- 1 -ynyllridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 3-(4-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (211 mg, 0.9 mmol) afforded 33 mg of 2-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5 yl)but- 1 -ynyl)pyridine (Yield : 11%) as brown oil. LCMS (RT) : 3.56min; MS (ES+) gave m/z: 320.1 1 H-NMiR (CDCl 3 ), 6 (ppm) : 8.57 (s, H), 7.80 (s, H), 7.28-7.26 (m, 4H), 6.87-6.83 (m, 2H), 4.02 (s, 2H), 3.78 (s, 3H), 3.24 (m, 2H), 2.96 (m, 2H). Example 21 2-(4-(3-Isopropyl-1 2,4-oxadiazol-5-v1)but-1-ynvl)pyridine 21(A) N'-Hydroxy-isobutyramidine According to- the general protocol for amidoxime synthesis described in Example 15(A), the conversion of isobutyronitrile (0.75 mL, 8 mmol) afforded 0.81 g of N' hydroxy-isobutyramidine (Yield: 99%) as colorless oil. 21(B) 5-(But-3-ynyl)-3-isopropyl-1,2.4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of N'-hydroxy-isobutyramidine (378 mg, 3.7 mmol) afforded 151 mg of 5-(but-3-ynyl)-3-isopropyl-1,2,4-oxadiazole (Yield: 25%) as yellow oil. LCMS (RT) : 3.16min; MS (ES+) gave m/z : 165.1 21(C) 2-(4-(3-Isopropyl-1,2,4-oxadiazol-5-vl)but-1-vnvl1pyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 5-(but-3-ynyl)-3-isopropyl-1,2,4-oxadiazole (151 mg, 0.9 mmol) afforded 62 mg of 2-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield : 29%) as brown oil. LCMS (RT) : 2.93min; MS (ES+) gave m/z: 242.1 'H-NMR (CDC1 3 ), S (ppm) : 8.57 (s, H), 7.80 (s, H), 7.50-7.30 (m, 2H), 3.27 (m, 2H), 3.12 (m, H), 2.98 (m, 2H), 1.36 (d, 6H).
WO 2005/123703 PCT/IB2005/002390 99 Example 22 2-(4-(3-Butvl-1,2,4-oxadiazol-5-yl)but-l-ynyl)pyridine 22(A) N'-Hydroxvpentanamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of pentanenitrile (0.85 mL, 8 mmol) afforded 0.91 g of N' hydroxypentanamidine (Yield: 98%) as colorless oil. 22(B) 5-(But-3-ynyl)-3-butyl-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of N'-hydroxypentanamidine (430 mg, 3.7 mmol) afforded 205 mg of 5-(but-3-ynyl)-3-butyl-1,2,4-oxadiazole (Yield: 31%) as yellow oil. LCMS (RT) : 3.75min; MS (ES+) gave m/z : 179.1 22(C) 2-(4-(3-Butyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pvridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 5-(but-3-ynyl)-3-butyl-1,2,4-oxadiazole (205 mg, 1.2 mmol) afforded 28 mg of 2-(4-(3-butyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield 9%) as brown oil. LCMS (RT) : 3.44min; MS (ES+) gave m/z : 256.1 'H-NMR (CDCl 3 ), 8 (ppm) : 8.57 (s, H), 7.65 (t, H), 7.40 (m, H), 7.25 (m, H), 3.23 (t, 2H), 2.98 (t, 2H), 2.74 (t, 2H), 1.74 (m, 2H), 1.40 (m, 2H), 0.94 (t, 3H). Example 23 2-(4-(3-(3-FluorobeUzyl)-1.2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 23(A) 2-(3-Fluorophenyl)-N'-hydroxyacetamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-(3-fluorophenyl)acetonitrile (0.94 nL, 8 mmol) afforded 1.34 g of 2-(3-fluorophenyl)-N'-hydroxyacetamidine (Yield : 99%) as yellow semi solid. 23(B) 3-(3-Fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of 2-(3-fluorophenyl)-N'-hydroxyacetamidine (622 mg, 3.7 minol) afforded 209 mg of 3-(3-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield : 25%) as yellow oil. LCMS (RT) : 4.03min; MS (ES+) gave m/z : 231.1 23(C) 2-(4-(3-(3-Fluorobenzyl)-1,2,4-oxadiazol-5-vl)but-1-yny1)pyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 3-(3-fluorobenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (209 mg, 0.9 mmol) afforded 63 mg of 2-(4-(3-(3-fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-l ynyl)pyridine (Yield: 23%) as brown oil. LCMS (RT) : 3.69min; MS (ES+) gave m/z : 308.1 'H-NMR (CDC1 3 ), 8 (ppm) : 8.57 (s, H), 7.70 (t, H), 7.32-7.24 (m, 3H), 7.12-7.09 (d, H), 7.06-7.02 (s, H), 6.98-6.92 (m, H), 4.07 (s, 2H), 3.21 (t, 2H), 2.96 (t, 2H).
WO 2005/123703 PCT/IB2005/002390 100 Example 24 2-(4-(3-(3-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 24(A) N'-Hydroxv-2-(3-methoxvphenyl)acetamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-(3-methoxyphenyl)acetonitrile (1.09 mL, 8 mmol) afforded 1.43 g of N'-hydroxy-2-(3-methoxyphenyl)acetamidine (Yield : 99%) as yellow oil. 24(B) 3-(3-Methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of N'-hydroxy-2-(3-methoxyphenyl)acetamidine (667 mg, 3.7 mmol) afforded 259 mg of 3-(3-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (Yield: 29%) as yellow oil. LCMS (RT) : 3.91min; MS (ES+) gave m/z: 243.1 24(C) 2-(4-(3-(3-Methoxvbenzyl-1,2,4-oxadiazol-5-y1)but-l-ynvl)pyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 3-(3-methoxybenzyl)-5-(but-3-ynyl)-1,2,4-oxadiazole (259 mg, 1.1 mmol) afforded 60 mg of 2-(4-(3-(3-methoxybenzyl)-1,2,4-oxadiazol-5 yl)but-l -ynyl)pyridine (Yield: 17%) as brown oil. LCMS (RT) : 3.64min; MS (ES+) gave m/z : 320.1 'H-NMR (CDC1 3 ), 8 (ppm) : 8.57 (s, H), 7.70 (t, H), 7.25-7.20 (m, 3H), 6.94-6.86 (m, 2H), 6.80 (m, H), 4.05 (s, 2H), 3.78 (s, 3H), 3.21 (t, 2H), 2.96 (t, 2H).. Example 25 2-(4-(3-(2-Fluorophenyl)-1,2.4-oxadiazol-5-vl)but-1-vny1)pyridine 25(A) 2-Fluoro-N'-hydroxybenzamidine According to the general protocol for amidoxine synthesis described in Example 15(A), the conversion of 2-fluorobenzonitrile (0.86 mL, 8 mmol) afforded 1.22 g of 2 fluoro-N'-hydroxybenzamidine (Yield: 99%) as yellow oil. 25(B) 5-(But-3-ynvl1-3-(2-fluorophenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of 2-fluoro-N'-hydroxybenzaniidine (570 mg, 3.7 mmol) afforded 405 mg of 5-(but-3-ynyl)-3-(2-fluorophenyl)-1,2,4-oxadiazole (Yield: 51%) as yellow oil. LCMS (RT) : 3.99min; MS (ES+) gave m/z : 217.1 25(C) 2-(4-(3-(2-Fluorophenvl)-1,2,4-oxadiazol-5-vl)but-1- ynvllpridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 5-(but-3-ynyl)-3-(2-fluoropheny)-1,2,4-oxadiazole (405 mg, 1.9 mmol) afforded 58 mg of 2-(4-(3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-l ynyl)pyridine (Yield: 10%) as brown oil. LCMS (RT) : 3.68min; MS (ES+) gave m/z : 294.1 'H-NMR (CDCl3), 5 (ppm) : 8.57 (s, H), 8.05 (t, H), 7.70 (m, H), 7.53-7.48 (m, H), 7.32-7.22 (m, 4H), 3.37 (m, 2H), 3.06 (m, 2H).
WO 2005/123703 PCT/IB2005/002390 101 Example 26 2-(4-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-y)but-1-Ynv1)pyridine 26(A) 3-Fluoro-N'-hydroxvbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 3-fluorobenzonitrile (0.65 mL, 8 mmol) afforded 0.97 g of 3 fluoro-N'-hydroxybenzamidine (Yield: 99%) as yellow oil. 26(B) 5-(But-3-yny1)-3-(3-fluorophenv1)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 15(B), the conversion of 3-fluoro-N'-hydroxybenzamidine (570 mg, 3.7 mmol) afforded 336 mg of 5-(but-3-ynyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (Yield : 42%) as yellow oil. LCMS (RT) : 4.3 1min; MS (ES+) gave m/z : 217.1 26(C) 2-(4-(3-(3-FluorophenyL)-1,2,4-oxadiazol-5-yl)but-1-yny13pyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 5-(but-3-ynyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (336 mg, 1.6 mmol) afforded 57 mg of 2-(4-(3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-l ynyl)pyridine (Yield: 12%) as brown oil. LCMS (RT) : 3.99min; MS (ES+) gave m/z : 294.1 'H-NNR (CDC1 3 ), S (ppm) : 8.57 (s, H), 7.90 (s, H), 7.80 (d, H), 7.70 (m, H), 7.53 7.48 (m, 2H), 7.32-7.18 (m, 2H), 3.33 (m, 2H), 3.07(m, 2H). Example 27 5-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzofdloxazole 27(A) Pent-4-ynimidic acid methyl ester Sodium (291 mg, 12.6 mmol) was dissolved in dry MeOH (40 mL). Pent-4-ynenitrile (2.00 g, 25.3 mmol) was added to the reaction mixture and the solution was stirred for 2 days at room temperature. Acetic acid (746 pL) was added followed by evaporation of the solvent to yield 1.20 g (10.8 mmol, 43%) of pent-4-ynimidic acid methyl ester as a white solid. 27(B) 2-(But-3-Ynyl)-5-chlorobenzoFdloxazole A mixture of pent-4-ynimidic acid methyl ester (142 mg, 1.28 mmol) and 2-amino-4 chlorophenol (227 mg, 1.53 mmol) in dichloroethane (10 mL) was stirred for 2 days under reflux. The solvent was evaporated, the residue was partly dissolved in MeOH and filtered. The filtrate was concentrated, and the resulting crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 18 mg (87 !lmol, 7%) of 2-(but-3-ynyl)-5-chlorobenzo[d]oxazole. 27(C) 5-Chloro-(2-(4-pyridin-2-vl)but-3-vnyl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (15 mg, 96 pmol) and 2-(but-3-ynyl)-5 chlorobenzo[d]oxazole (18 mg, 87 pLmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 6.5 mg (23 pmol, 26%) of 5-chloro-(2-(4-pyridin-2-yl)but-3-yny)benzo[d]oxazole as a yellow solid. LCMS (RT) : 3.84min; MS (ES+) gave m/z : 283.0, 285.0.
WO 2005/123703 PCT/IB2005/002390 102 1H-NMR (CDC1 3 ), 5 (ppm) : 3.11 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H), 7.30 (dd, J=2.5 and 9.0, 1H), 7.33-7.41 (in, 1H), 7.43 (d, J=9.0, 1H), 7.48 (d, J=7.5, 1H), 7.67 (d, J=1.5, 111), 7.79-7.87 (in, 1H), 8.60 (d, J=5.0, 1H). Example 28 5-Methyl-(2-(4-pyridin-2-yl)but-3 -nv1)benzo[dloxazole 28(A) 2-(But-3-vnyl)-5-methylbenzofdloxazole The title compound was prepared in accordance with the general method of Example 27(B) from 2-amino-4-methylphenol (181 mg, 1.43 mmol). The resulting crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 19 mg (0.1 mmol, 7%) of 2-(but-3-yny)-5-methylbenzo[d]oxazole. 28(B) 5-Methyl-(2-(4-pyridin-2-vl)but-3-vnyl)benzofdloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (16 mg, 0.1 mmol) and 2-(but-3-ynyl)-5 methylbenzo[d]oxazole (19 ing, 0.1 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NT40H 90:10:0.1 to 88:10:2) to yield 2.0 mg (7.6 ptmol, 8%) of 5-methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[dloxazole as a yellow solid. LCMS (RT) : 3.63min; MS (ES+) gave m/z : 263.1. Rf (DCM/MeOH 97:3) = 0.1. Example 29 6-Methyl-(2-(4-pyridin-2-yl)but-3-ynv1)benzordloxazole 29(A) 2-(But-3-ynyl)-6-methylbenzordloxazole The title compound was prepared in accordance with the general method of Example 27(B) from 2-amino-5-methylphenol (192 mg, 1.52 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 14 mg (77 pLmol, 6%) of 2-(but-3-ynyl)-6-methylbenzo[d]oxazole. 29(B) 6-Methyl-(2-(4-pyridin-2-vl)but-3-ynvl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (14 mg, 89 pmol) and 2-(but-3-ynyl)-6 methylbenzo[d]oxazole (15 mg, 81 tmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH 4 0H 90:10:0.1 to 88:10:2) to yield 7.0 ing (27 ptmol, 33%) of 6-methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid. LCMS (RT) : 3.53min; MS (ES+) gave m/z : 263.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.48 (s, 3H), 3.09 (t, J=7.5, 2H), 3.30 (t, J=7.5, 2H), 7.13 (d, J=8.0, 111), 7.30 (s, 1H), 7.31-7.37 (in, 1H), 7.46 (d, J=8.0, 1H), 7.55 (d, J=8.0, 1H), 7.75-7.82 (in, 1H), 8.59 (d, J=5.0, 1H).
WO 2005/123703 PCT/IB2005/002390 103 Example 30 4-Methyl-(2-(4-pyridin-2-yl)but-3-vnv1)benzo [dloxazole 30(A) 2-(But-3-vnyl)-4-methylbenzo[dloxazole The title compound was prepared in accordance with the general method of Example 27(B) from 2-amino-3-methylphenol (183 mg, 1.48 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 12 mg (66 tmol, 5%) of 2-(but-3-ynyl)-4-methylbenzo[d]oxazole. 30(B) 4-Methyl-(2-(4-pyridin-2-yl)but-3-yL)benzordloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (12 mg, 77 kmol) and 2-(but-3-ynyl)-4 methylbenzo[d]oxazole (13 mg, 70 pumol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH 4 0H 90:5:0.1 to 87:10:3) to yield 7.0 mg (27 tmol, 38%) of 4-methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid. LCMS (RT): 3.61min; MS (ES+) gave m/z: 263.1. 1 H-NMR (CDC1 3 ), 5 (ppm) : 2.60 (s, 3H), 3.11 (t, J=8.0, 2H), 3.33 (t, J=8.0, 2H), 7.11 (d, J=7.5, 111), 7.17-7.24 (m, 1H), 7.32 (d, J=7.5, 1H), 7.37-7.45 (m, 1H), 7.50 (d, J=8.0, 1H), 7.81-7.90 (m, 1H), 8.61 (d, J=4.5, 1H). Example 31 2-(4-(2-Methylthiazol-4-yl)but-3-vyllbenzordloxazole The title compound was prepared in accordance with the general method of Example 1, from 4-bromo-2-methylthiazole (47 mg, 2.7 mmol) and 2-(but-3 ynyl)benzo[d]oxazole (454 mg, 2.65 mmol, Example 8(A)). The reaction mixture was stirred for one day under reflux. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) and trituration with pentane to yield 14 mg (52 pLmol, 2%) of 2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]oxazole as a beige solid. Example 32 2-(4-(5-Phenyl-2H-tetrazol-2-vl)but-1-ynyl)pyridine 32(A) 4-(Pyridin-2-v1)but-3-yn-1-ol In a dry reaction tube containing in suspension iodide copper (38 mg, 0.2 mmol) and triethylamine (11 mL, 80 mmol), were added 2-bromopyridine (632 mg, 4 mmol) and Pd(PPh 3
)
2
C
2 (140 mg, 0.2 mmol). A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution of but-3-yn-1-ol (280 mg, 4 mmol) in triethylamine (2.2 mL). Immediatly the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 80'C for 20h. Triethylamine was concentrated under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH 4 C1, water and brine, dried (MgSO 4 ) and concentrated. The product was purified by flash chromatography (prepacked 15 g silicagel column, from DCM 100% to DCM/MeOH WO 2005/123703 PCT/IB2005/002390 104 98/2 as eluent) to afford 440 mg of 4-(pyridin-2-yl)but-3-yn-1-ol (Yield : 74%) as brown oil. Rf:(DCM/MeOH : 95/5) = 0.5 LCMS (RT) : 0.60min; MS (ES+) gave m/z: 148.1 32(B) 2-(4-(5-Pheny1-2H-tetrazol-2-yl)but-1-ynyllpyridine A mixture of 5-phenyl-2H-tetrazole (330 mg, 2.2 mmol), 4-(pyridin-2-yl)but-3-yn-l ol (220 mg, 1.49 mmol) and triphenylphosphine polymer supported (750 mg, 2.2 mmol, loading 3mmol/g) were dissolved DCM (3 mL) and stirred at 0 0 C. Diisoprpylazodicarboxylate (452 mg, 2.2 mmol) was added dropwise, at 0 0 C over a period of 30min. The reaction mixture was then warmed to room temperature and stirred over night. The reaction mixture was filtered through celite and the cake was washed with DCM. The combined organic layers were washed with aqueous ammoniac, brine, dried over MgSO 4 , filtered and concentrated. The residue was purified by flash chromatography (prepacked 25g silicagel column, DCM 100% as eluent) to afford 209 mg of 2-(4-(5-phenyl-2H-tetrazol-2-yl)but-l-ynyl)pyridine (Yield: 51%) as a pink powder (M.P. = 71-73'C). Rf (DCM/MeOH: 97/3)= 0.4 LCMS (RT) : 3.74min; MS (ES+) gave m/z : 276.1 'NMR (CDC13), 5 (ppm) : 8.64 (s, H), 8.17 (in, H), 7.63 (t, H), 7.53-7.46 (in, 2H), 7.36 (d, H), 7.25-7.20 (in, H), 6.36 (in, 2H), 4.93 (t, 2H), 3.25 (t, 2H). Example 33 2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-alpyridine 33(A) Ethyl inidazo[1,2-alpyridine-2-carboxylate A solution of 2-amino-pyridine (2 g, 21 mmol) and ethyl bromopyruvate (4.14 g, 21 mmol) in ethanol (31 mL) was stirred under reflux for 24 h. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH = 8) with saturated NaHCO 3 . The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was removed under pressure to afford 2.51 g of ethyl inidazo[1,2-a]pyridine 2-carboxylate (Yield : 62%) as an orange oil which can be used without further purification. LCMS (RT) : 0.72-1.39min; MS (ES+) gave m/z: 191.1 Rf (DCM/MeOH: 95/5) : 0.12 33(B) 2-Hydroxymethyl-imidazor1.2-alpyridine In a dry round flask is added LiA1H 4 (650 mg, 17 minol) in anhydrous THF (52 mL) under stirring. The solution was cooled to OC. A solution of ethyl imidazo[1,2 a]pyridine-2-carboxylate (2.5 g, 13 mmol) in dry THF (3 mL) was added dropwise. The solution became green. The reaction mixture was stirred at 0 0 C for 30min and 2h at R.T. The reaction mixture was quenched with successively 0.52 mL of water, 0.52 mL of NaOH 1M and 3x0.52 mL of water. The solution is filtered over celite. The organic layer is evaporated to give 2.25 g of an orange liquid. The residue was purified by flash chhromatography over silicagel (prepacked 70 g silicagel column, DCM/MeOH : 95/5 as eluent) to afford 1 g of 2-hydroxymethyl-imidazo[1,2 a]pyridine (Yield: 51%) as a brown il. LCMS (RT): 0.62; MS (ES+) gave m/z: 149.1 WO 2005/123703 PCT/IB2005/002390 105 Rf (DCM/MeOH: 95/5): 0.13 33(C) 2-(Chloromethy1)-imidazo[1,2-alpyridine In a round bottomed flask containing 2-hydroxymethyl-imidazo[1,2-a]pyridine (800 mg, 5.4 mmol) in DCM (8 mL), was added at R.T. thionyl chloride (1.96 mL, 27 mmol). The solution became clear and 10min later, a precipitated was formed. The reaction mixture was stirred at R.T. for 2 hours and the solvent was removed under reduced pressure to afford 1.10 g of a brownish solid as the chlorhydrate form of 2 (chloromethyl)-imidazo[1,2-a]pyridine (Yield : 100%). To saturated NaHCO 3 (40mL) was added the chlorhydrate form of 2-(chloromethyl) imidazo[1,2-a]pyridine and the aqueous layer was extracted with AcOEt. The organic layers were combined and washed with brine, dried over MgSO 4 and the solvent was removed under reduced pressure to afford 877 mg of 2-(chloromethyl)-imidazo[1,2 a]pyridine (Yield. 80%).as a brownish solid (M.P. : 84-85'C) LCMS (RT) : 0.64; MS (ES+) gave m/z: 167.1 33(D) 2-(4-(Trimethylsilyl-but-3-ynyl)-imidazof1,2-alpyridine According to the protocol described in Example 38(C), the conversion of 2 (chloromethyl)-imidazo[1,2-alpyridine (200 mg, 1.2 mmol) afforded 155 mg of 2-(4 (trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 53%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 99/1 to 98/2 as eluent). LCMS (RT) : 0.54-2.71min; MS (ES+) gave m/z : 243.1 Rf (DCM/MeOH: 95/5) : 0.42 33(E) 2-(But-3-ynl)-imidazo[1,2-alpyridine According to the protocol described in Example 38(D), the conversion of 2-(4 (trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (140 mg, 0.67 mmol) afforded 70 mg of 2-(but-3-ynyl)-inidazo[1,2-a]pyridine (Yield : 71%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 99/1 to 98/2 as eluent). LCMS (RT) : 0.54min; MS (ES+) gave m/z : 171.1 Rf (DCM/MeOH: 95/5) : 0.27 33(F) 2-(4-(Pyridin-2-y1)but-3-ynyl)-imidazo[1,2-alpyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (70 mg, 0.41 mmol) afforded 34 mg of 2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield 33%) as yellow oil. Purification over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent). LCMS (RT) : 0.60-1.57min; MS (ES+) gave m/z : 248.1 Rf (DCM/MeOH: 95/5) : 0.32 'H-NMR (CDC1 3 ), 8 (ppm) : 8.54 (d, H), 8.06 (d, H), 7.64-7.57 (m, 2H), 7.50 (s, H), 7.40 (d, H), 7.20-7.12 (m, 2H), 6.75 (t, H), 3.13 (t, 2H), 2.93 (t, 2H).
WO 2005/123703 PCT/IB2005/002390 106 Example 34 N-(4-Fluorophenyl)-5-(pyridine-2-y1)pent-4-ynamide 34(A) N-(4-Fluorophen1)pent-4-namide According to the protocol described in Example 12(A), the conversion of N 4 fluorobenzenamine (566 mg, 5.10 mmol) afforded 922 mg of N-(4-fluorophenyl)pent 4-ynamide (Yield : 95%) as brownish solid which can be used without further purification.. LCMS (RT) : 0.64min; MS (ES+) gave m/z: 1 92 .1 Rf (DCM/MeOH: 8/2) = 0.2 34(B) tert-Butyl 4-fluorophenylpent-4-ynoylcarbamate According to the general protocol described in J. Med. Chem., 2000, 43, 20, 3718 3735, to solution of N-(4-fluorophenyl)pent-4-ynamide (200 mg, 1 mmol) in DCM (3 mL) were successively added triethylamine (146 mL, 1.05 mmol), (BOC) 2 0 (270 mg, 1.3 mmol) and DMAP (13 mg, 0.1 mmol). After stirring for 18h at room temperature, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : 90/10 as eluent) to afford 274 mg of tert-butyl 4-fluorophenylpent-4-ynoylcarbamate (Yield: 90%) as colorless oil. LCMS (RT) : 4.11min; MS (ES+) gave m/z : 192.1 (MH+-Boc) Rf (Cyclohexane/AcOEt: 90/10): 0.35 34(C) tert-Butyl 5-(pyridin-2-yl)pent-4-ynoy4-fluorophenylcarbamate According to the protocol described in Example 38(E), the conversion of tert-butyl 4 fluorophenylpent-4-ynoylcarbanate (274 mg, 0.94 mmol) afforded 299 mg of tert butyl 5-(pyridin-2-y1)pent-4-ynoy14-fluorophenylcarbamate (Yield : 86%) as yellow oil. Purification by Flash chromatography (prepacked 25 g silicagel column, DCM/MeOH : 99/1 as eluent) LCMS (RT) : 3.94min; MS (ES+) gave m/z: 369 Rf (DCM/MeOH: 98/2) : 0.19 34(D) N-(4-Fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamfide tert-Butyl-5-(pyridin-2-yl)pent-4-ynoy14-fluorophenylearbamate (299 mg, 0.81 mmol) was dissolved in DCM (4 mL) with 0.01% w/w of water. 4mL of trifluoroacetic acid was added at room temperature to the solution. The resulting mixture was stirred at R.T. for 2h. The solvent was removed under reduced pressure. The brown oil was dissolved in saturated NaHCO 3 until pH = 8. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4 and the solvent was removed under reduced pressure. The brownish solid was tritureted in a mixture Et 2 O/Pentane : 50/50. The solid was collected by filtration and washed with a mixture Et 2 O/Pentane : 50/50. The solid was dried by lyophilisation to afford 181 mg of N-(4-fluorophenyl)-5-(pyridine-2-yl)pent 4-ynamide (Yield: 83%) as a colorless solid (M.P.= 189.9-190.2'C). LCMS (RT) : 2.83min; MS (ES+) gave m/z : 269.1 Rf (DCM/MeOH : 95/5) : 0.23 'NMR (CDC1 3 ), S (ppm) : 8.56 (s, H), 7.68-7.61 (m, 2H), 7.54-7.49 (m, 211), 7.38 (d, H), 7.23 (m, H), 7.11 (m, 2H), 2.88 (t, 2H), 2.70 (t, 2H).
WO 2005/123703 PCT/IB2005/002390 107 Example 35 2-(4-(Pyridin-2-yllbut-3-ynyl)benzordlthiazole 35(A) 2-(But-3-ynyl)benzofdlthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-aminobenzenethiol (387 mg, 3.03 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 453 mg (2.42 mmol, 80%) of 2-(but-3-ynyl)benzo[d]thiazole as an orange oil. 35(B) 2-(4-(Pyridin-2-y)but-3-vnyl)benzordlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (127 mg, 0.80 mmol) and 2-(but-3-ynyl)benzo[d]thiazole (150 mg, 0.80 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 96 mg (0.36 mmol, 45%) of 2-(4 (pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orange solid (M.P. = 98.5-99.4'C). LCMS (RT) : 3.24min; MS (ES+) gave m/z : 265.0. Rf (DCM/MeOH 99:1) = 0.2. 'H-NMR (CDC1 3 ), S (ppm) : 3.05 (t, J=7.5, 2H), 3.46 (t, J=7.5, 2H), 7.18-7.22 (m, 1H), 7.35-7.39 (2H), 7.45-7.49 (m, 1H), 7.60-7.64 (m, 1H), 7.84-7.87 (m, 1H), 7.99 (d, J=8.0, 1H), 8.54-8.57 (m, 1H). Example 36 6-Chloro-(2-(4-pvridin-2-v1)but-3-vnv1)benzordloxazole 36(A) 2-(But-3-ynv1)-6-chlorobenzordloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-5-chlorophenol (290 mg, 2.02 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 262 mg (1.28 mmol, 65%) of 2-(but-3-ynyl)-6-chlorobenzo[d]oxazole as an orange solid. 36(B) 6-Chloro-(2-(4-yridin-2-v1)but-3-vnv1)benzordloxazol The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (115 mg, 0.73 mmol) and 2-(but-3-ynyl)-6 .chlorobenzo[d]oxazole (150 mg, 0.73 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 107 mg (0.38 mmol, 52%) of 6-chloro (2-(4-pyridin-2-y1)but-3-yny1)benzo[d]oxazole as a yellow solid (M.P. = 101.5 102.2-C). LCMS (RT) : 3.49min; MS (ES+) gave m/z : 283.0,285.0. Rf (DCM/MeOH 99:1) = 0.2. 'H-NMR (CDC1 3 ), S (ppm) : 3.05 (t, J=7.5, 2H), 3.28 (t, J=7.5, 2H), 7.18-7.22 (m, 1H), 7.29 (dd, J=2.0 and 8.5, 1H), 7.33-7.36 (m, 1H), 7.51 (d, J=2.0, 1H), 7.59 (d, J=9.0, 1H), 7.59-7.63 (m, 1H), 8.53-8.55 (m, 1H).
WO 2005/123703 PCT/IB2005/002390 108 Example 37 5-Fluoro-(2-(4-pyridin-2-vl)but-3-yny1)benzo[dloxazole 37(A) 2-(But-3-ynyl)-5-fluorobenzo[dloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-4-fluorophenol (259 mg, 2.04 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 116 mg (0.61 mmol, 30%) of 2-(but-3-ynyl)-5-fluorobenzo[d]oxazole as a yellow solid. 37(B) 5-Fluoro-(2-(4-pyridin-2-vl)but-3-vnvl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (96.9 mg, 0.61 mmol) and 2-(but-3-ynyl)-5 fluorobenzo[d]oxazole (116 mg, 0.61 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 84 mg (0.31 mmol, 51%) of 5-fluoro-(2 (4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a slightly yellow solid (M.P. = 100.1 101.0-C). LCMS (RT) : 3.11min; MS (ES+) gave m/z : 267.1. Rf (DCM/MeOH 99:1) = 0.2. 1 H-NMR (CDC1 3 ), 6 (ppm) : 3.06 (t, J=6.5, 2H), 3.29 (t, J=6.5, 2H), 7.02-7.07 (m, 1H), 7.18-7.21 (m, IH), 7.34-7.39 (2H), 7.43 (dd, J=4.5 and 9.0, 1H), 7.59-7.63 (m, 1H), 8.52-8.55 (m, 1H). Example 38 2-(6-(4-Fluorophenv1)hexa-1,5-divnvl)pyridine 38(A) 3-(4-Fluorophenvl)prop-2-vn-1-ol In a dry flask containing in suspension copper iodide (84 mg, 0.44 mmol) and triethylamine (24.70 mL), was added Pd(PPh 3
)
2 C1 2 (310 mg, 0.44 mmol) under N 2 . A yellow suspension is obtained. The reaction mixture was cooled to 0 0 C in an ice-bath before the addition of 1-fluoro-4-iodobenzene (1.95 g, 8.80 mmol). After five minutes at 0 0 C, a solution of prop-2-yn-1-ol (493 mg, 8.80 mmol) in triethylamine (4 mL) was slowly added under N 2 over a period of 15 min. Immediately the color of the reaction turns to black. The mixture was stirred 0 0 C for 30 min and then warmed to room temperature for 20h under N 2 . Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated
NH
4 Cl, water, brine, dried (MgSO 4 ) and concentrated. The crude product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100 % as eluent) to afford 1.10 g of 3-(4-fluorophenyl)prop-2-yn-1-ol (Yield : 83%) as a yellow oil. Rf (DCM/MeOH : 95/5)= 0.5 LCMS (RT) : 2.88min, MS (ES+) : no ionisation 38(B) 1-(3-Bromoprop-1-yny1)-4-fluorobenzene A solution of 3-(4-fluorophenyl)prop-2-yn-1-ol (1 g, 6.80 mmol) in DCM (13.6 mL) under N 2 was cooled in a ice bath at 0 0 C. 2.70 g (8.2 mmol, loading 3mmol/g) of triphenylphosphine polymer supported was then added followed by 2.70 g (8.2 mmol) of carbon tetrabromide. The reaction mixture was stirred 15min at 0 0 C and warmed to room temperature for 90min. After filtration throughr celite, the solvent was evaporated under reduce pressure. The crude product was purified by flash WO 2005/123703 PCT/IB2005/002390 109 chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.44 g of 1-(3-bromoprop-1-ynyl)-4-fluorobenzene as a yellow oil (Yield: 99%). Rf (DCM/MeOH : 95/5) = 0.6 LCMS (RT) : 4.14min, MS (ES+) : no ionisation 38(C) (6-(4-Fluorophenvl)hexa-1,5-diynyl trimethylsilane To a solution of trimethyl(prop-l-ynyl)silane (2.19 g, 19.50 mmol) in 22 mL of THE at -78'C, was added dropwise n-BuLi 2.5M in hexane (7.8 mL, 20 mmol). After stirring 2 hoursat -78'C, 1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THF was slowly added and the resulting mixture was stirred for lh at 78'C and warmed to room temperature for an additional lh. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgS04, filtered and concentrated to afford 1.57 g of (6-(4-fluorophenyl)hexa 1,5-diynyl)trimethylsilane (99%) as a yellow oil. LCMS (RT): 4.89min, MS (ES+) : no ionisation 38(D) 1-Fluoro-4-(hexa-1,5-divnv1)benzene To a solution of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (1.90 g, 7.7 mmol) in THF (24 mL) cooled in a ice bath at 0 0 C, was added dropwise 7.7 mL of tetrabutylammonium fluoride IM in THE solution (7.70 mmol). The reaction mixture was stirred 15 min at 0 0 C, and warmed to room temperature for 2h30. The reaction was quenched with water and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated. The product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 500 mg of 1-fluoro-4-(hexa-1,5-diynyl)benzene (Yield: 45%) as a yellow oil. LCMS (RT) : 4.1 1min, MS (ES+) : no ionisation 38(E) 2-(6-(4-Fluorophenvl)hexa-1,5-divnvl)pyridine In a dry reaction tube containing in suspension copper iodide (11 mg, 0.06 mmol) and triethylamine (3.4 mL), were added 2-iodopyridine (246 mg, 1.2 mmol) and Pd(PPh 3
)
2
C
2 (42 mg, 0.06 mmol) under N 2 . A yellow suspension was obtained after 5min of stirring at room temperature. A solution of 1-fluoro-4-(hexa-1,5 diynyl)benzene (210 mg, 1.2 mmol) in triethylamine (0.5 mL) was then added under
N
2 . Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 48h. The reaction mixture was concentrated. The crude product was dissolved in DCM and the organic phase was washed with saturated NH 4 Cl, water and brine. The organic layer was dried over MgS04, filtered, and concentrated. Purification by Flash chromatography (prepacked 25 g silicagel column, Cyclohexane/ethyl acetate from 90/10to 80/20 as eluent) to afford 87 mg of 2-(6-(4 fluorophenyl)hexa-1,5-diynyl)pyridine (Yield : 29%) as a brown powder (M.P. = 68 69-C). Rf (Cyclohexane/AcOEt: 80/20) = 0.3 LCMS (RT): 3.91min; MS (ES+) gave m/z : 250.1 1 NMR (CDC1 3 ), 5 (ppm) : 8.58 (d, H), 7.63 (t, H), 7.42-7.37 (m, 3H), 7.22 (in, H), 7.01-6.95 (m, 2H), 2.76 (in, 4H)..
WO 2005/123703 PCT/IB2005/002390 110 Example 39 2-(4-(Pyridin-2-yl)but-3-ynyl)-[1,2,41triazoloF4,3-alpyridin-3(2H)-one 39(A) 2-(But-3-ynyl)-[1,2,41triazolo[4,3-alpyridin-3(2H)-one The title compound was prepared in accordance with the general method of Example 109(D), from [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (405 mg, 3.00 mmol) and but-3 yn-1-ol (200 mg, 2.85 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 140 mg (0.75 mmol, 26%) of 2-(but-3 ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. 39(B) 2-(4-(Pyridin-2-yl)but-3-nlV)-1,2,41triazolof4,3-alpyridin-3(2H)-one The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-apyridin-3(2H)-one (70 mg, 0.37 mmol) and 2-bromopyridine (65 mg, 0.41 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2).to yield 23 mg (87 prmol, 23%) of 2-(4-(pyridin 2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a yellow solid (M.P. = 95.5-96-C). LCMS (RT) : 2.43min; MS (ES+) gave m/z: 265.0. Rf (DCM/MeOH 98:2) = 0.1. 'H-NMR (CDCl 3 ), 5 (ppm) : 3.00 (t, J=7.2, 2H), 4.29 (t, J=7.2, 2H), 6.46-6.51 (m, 1H), 7.08-7.11 (2H), 7.19 (ddd, J=1.1, 4.8 and 7.8, 1H), 7.38 (d, J=8.1, 1H), 7.57-7.65 (, 111), 7.73-7.78 (m, 1H), 8.50-8.55 (m, 1H). Example 40 2-(4-(3-(2-Methoxyphenyl)-1,2,4-oxadiazol-5-y1)but-1-ynyl)pyridine 40(A) N'-Hydroxy-2-methoxybenzanidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-methoxybenzonitrile (0.86 mL, 7 mmol) afforded 1.1g of N'-hydroxy-2-methoxybenzamidine (Yield: 95%) as white powder (M.P. = 66-68'C). 40(B) 5-(But-3-ynyl)-3-(2-methoxyphenyl)-1,2,4-oxadiazole In a reactor tube, a mixture of N'-hydroxy-2-methoxybenzarnidine (598 mg, 3.6 mmol), 4-pentynoic acid (350 mg, 3.6 mmol), HOBT (0.55 g, 3.6 mmol) and EDCI.HC1 (1.03 g, 5.4 mmol) in dioxane (7.4 mL) was stirred at R.T for 3h. After this time the mixture was heated at 80'C overnight in a reaction block. The mixture was concentrated and the crude product was purified by flash chromatography (Prepacked column 25 g with DCM as eluent) to afford 299 mg of 5-(but-3-ynyl)-3-(2 methoxyphenyl)-1,2,4-oxadiazole (36%) as yellow oil. LCMS (RT) : 3.39min; MS (ES+) gave m/z : 229.0 Rf Oxadiazole (DCM/MeOH : 99/1) : 0.75. 40(C) 2-(4-(3-(2-Methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine In a dry reaction tube containing in suspension copper iodide (12 mg, 0.07 mmol) and triethylamine (4.1 mL, 29 mimol), were added 2-iodopyridine (139 ptL, 1.3 mmol) and Pd(PPh 3
)
2 Cl 2 (46 mg, 0.07 mmol) under N 2 . A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution 5-(but-3-ynyl)-3 (2-methoxyphenyl)-1,2,4-oxadiazole (299 mg, 1.3 mmol) in triethylamine(0.7 mL) WO 2005/123703 PCT/IB2005/002390 111 under N 2 . Imediatly the color of the reaction turns to black. The mixture was stirred at room temperature for 20h under N 2 . Triethylamine was removed under reduce pressure and the crude product was purified by flash chromatography (Prepacked column 10 g, cyclohexane/AcOEt : from 60/40 to 50/50 as eluent) to afford 50 mg of 2-(4-(3-(2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (13%) as brown oil. LCMS (RT) : 3.04min; MS (ES+) gave m/z : 306.1 'H-NMR (CDC1 3 ), S (ppm) : 8.56 (d, H), 8.01 (dd, H), 7.62 (t, H), 7.48 (t, H), 7.38 (d, H), 7.23-7.18 (m, H), 7.11-7.04 (m, 2H), 3.98 (s, 3H), 3.32 (t, 2H), 3.06 (t, 2H). Example 41 2-(4-(3-(3-Methoxyphenv1)-1,2,4-oxadiazol-5-vl)but-1-vny1)pyridine 41(A) N'-Hydroxv-3-methoxybenzanidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 3-methoxybenzonitrile (0.87 mL, 7 mmol) afforded 1.1 g of N'-hydroxy-3-methoxybenzamidine (Yield: 95%) as beige powder (M.P. = 59-61'C). 41(B) 5-(But-3-nynl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-3-methoxybenzamidine (598 mg, 3.6 mmol) afforded 276 mg of 5-(but-3-ynyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole (Yield 34%) as yellow oil. LCMS (RT) : 3.79min; MS (ES+) gave m/z : 229.0 41(C) 2-(4-(3-(3-Methoxyphenyl)-1,2,4-oxadiazol-5-vl)but-1-yny1)pvridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole (276 mg, 1.2 mmol) afforded 128 mg of 2-(4-(3-(3-methoxyphenyl)-1,2,4-oxadiazol-5 yl)but-1-ynyl)pyridine (Yield : 35%) as brown oil. LCMS (RT) : 3.59min; MS (ES+) gave m/z : 306.1 'H-NMR (CDC1 3 ), S (ppm) : 8.56 (d, H), 7.68 (d, H), 7.65-7.60 (m, 2H), 7.41-7.36 (m, 2H), 7.22 (m, H), 7.06 (d, H), 3.88 (s, 3H), 3.32 (t, 2H), 3.06 (t, 2H). Example 42 2-(4-(3-(4-Methoxyphenvl)-1,2,4-oxadiazol-5-vl)but-1-vnyl)pyridine 42(A) N'-Hydroxv-4-methoxvbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 4-methoxybenzonitrile (0.93 g, 7 nnol) afforded 1.1 g of N'-hydroxy-4-inethoxybenzamidine (Yield : 95%) as beige powder (M.P. = 113 115*C). 42(B) 5-(But-3-vnvl)-3-(4-methoxvphenvl)-l.2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-4-methoxybenzamidine (598 mg, 3.6 mmol) afforded 343 mg of 5-(but-3-yny1)-3-(4-methoxypheny1)-1,2,4-oxadiazole (Yield 42%) as yellow oil. LCMS (RT) : 3.81min; MS (ES+) gave m/z : 229.0 WO 2005/123703 PCT/IB2005/002390 112 42(C) 2-(4-(3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-y1)but-1-vnylpyridine According to the general protocol for Sonogasbira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(4-methoxyphenyl)-1,2,4-oxadiazole (343 mg, 1.5 mmol) afforded 98 mg of 2-(4-(3-(4-methoxyphenyl)-1,2,4-oxadiazol-5 yl)but-l-ynyl)pyridine (Yield : 21%) as brown oil. LCMS (RT) : 3.51min; MS (ES+) gave m/z : 306.1 'H-NMR (CDC13), 6 (ppm) : 8.56 (d, H), 8.01-8.05 (m, 2H), 7.62 (t, H), 7.38(d, H), 7.22 (m, H), 7.02-6.97 (m, 2H), 3.88 (s, 3H), 3.28 (t, 2H), 3.04 (t, 2H). Example 43 2-(4-(3-m-Tolyl-1,2,4-oxadiazol-5-yv1but-1-vnvl)pvridine 43(A) N'-Hydroxy-3-methylbenzanidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 3-methylbenzonitrile (0.83 mL, 7 mmol) afforded 1.03 g of N'-hydroxy-3-methylbenzamidine (Yield: 98%) as beige powder (M.P. = 86-88'C). 43(B) 5-(But-3-ynyl)-3-m-tolvl-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-3-methylbenzamidine (541 mg, 3.6 mmol) afforded 226 mg of 5-(but-3-ynyl)-3-m-tolyl-1,2,4-oxadiazole (Yield: 30%) as yellow oil. LCMS (RT) : 3.98min; MS (ES+) gave m/z : 213.1 43(C) 2-(4-(3-m-Tolvl-1,2,4-oxadiazol-5-v1)but-1-yny1)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-m-tolyl-1,2,4-oxadiazole (226 mg, 1.1 mmol) afforded 144 mg of 2-(4-(3-m-tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield : 45%) as brown oil. LCMS (RT) : 3.76min; MS (ES+) gave m/z : 290.1 'NMR (CDC1 3 ), S (ppm) : 8.56 (d, H), 7.93- 7.87(m, 2H), 7.62 (t, H), 7.41-7.36(m, 2H), 7.32 (m, H), 7.22 (m, H), 3.31 (t, 2H), 3.06 (t, 2H), 2.43 (s, 3H). Example 44 2-(4-(3-p-Tolyl-1,2,4-oxadiazol-5-y1)but-1-n1)pyridine 44(A) N'-Hydroxy-4-methylbenzamqidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 4-methylbenzonitrile (0.82 g, 7 mmol) afforded 1.03 g of N' hydroxy-4-methylbenzanidine (Yield: 98%) as white powder (M.P. = 143-144'C). 44(B) 5-(But-3-vnvl)-3-p-tolvl-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-4-methylbenzamidine (541 mg, 3.6 mmol) afforded 482 mg of 5-(but-3-ynyl)-3-p-tolyl-1,2,4-oxadiazole (Yield: 63%) as yellow oil. LCMS (RT) : 3.99min; MS (ES+) gave m/z: 213.1 WO 2005/123703 PCT/IB2005/002390 113 44(C) 2-(4-(3-p-Tolyl-1,2,4-oxadiazol-5-v1)but-1-ynyl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-p-tolyl-1,2,4-oxadiazole (482 mg, 2.3 mmol) afforded 175 mg of 2-(4-(3-p-tolyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield : 26%) as brown oil. LCMS (RT) : 3.76min; MS (ES+) gave m/z: 290.1 1 NMR (CDC1 3 ), S (ppm) : 8.56 (d, H), 7.93-7.87(m, 2H), 7.62 (t, H), 7.38 (d, H), 7.32-7.28 (m, 2H), 7.22 (m, H), 3.31 (t, 2H), 3.06 (t, 2H), 2.42 (s, 3H). Example 45 2-(4-(3-(2-Chlorophenl)-L,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 45(A) 2-Chloro-N'-hydroxvbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-chlorobenzonitrile (0.96 g, 7 mmol) afforded 1.01 g of 2 chloro-N'-hydroxybenzamidine (Yield: 85%) as beige powder (M.P. = 79-81'C). 45(B) 5-(But-3-vnL1)-3-(2-cblorophenv1)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 2-chloro-N'-hydroxybenzamidine (614 mg, 3.6 mmol) afforded 210 mg of 5-(but-3-ynyl)-3-(2-cblorophenyl)-1,2,4-oxadiazole (Yield : 25%) as yellow oil. LCMS (RT) : 3.83min; MS (ES+) gave m/z : 233.0 45(C) 2-(4-(3-(2-Chlorophenl)-1,2,4-oxadiazol-5-vl)but-1-ynyl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2-chlorophenyl)-1,2,4-oxadiazole (210 mg, 0.9 mmol) afforded 124 mg of 2-(4-(3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1 ynyl)pyridine (Yield : 45%) as brown oil. LCMS (RT) : 3.59min; MS (ES+) gave m/z: 310.1 1 NMR (CDC1 3 ), S (ppm): 8.56 (d, H), 7.93 (d, H), 7.62 (t, H), 7.48-7.37 (m, 3H), 7.22 (m, H), 7.22 (m, H), 3.35 (t, 2H), 3.08 (t, 2H). Example 46 2-(4-(3-(3-Clorophenvl)-1,2,4-oxadiazol-5-v1)but-1-ynl)pyridine 46(A) 3-Chloro-N'-hydroxybenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 3-chlorobenzonitrile (0.96 g, 7 mmol) afforded 1.18 g of 3 chloro-N'-hydroxybenzamidine (Yield: 99%) as beige powder (M.P. = 103-105'C). 46(B) 5-(But-3-yny1)-3-(3-chloropheny1)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 3-chloro-N'-hydroxybenzamidine (614 mg, 3.6 mmol) afforded 344 mg of 5-(but-3-ynyl)-3-(3-chlorophenyl)-1,2,4-oxadiazole (Yield: 41%) as yellow oil. LCMS (RT) : 4.l4min; MS (ES+) gave m/z : 233.0 WO 2005/123703 PCT/IB2005/002390 114 46(C) 2-(4-(3-(3-Chlorophenvl1-1,2,4-oxadiazol-5-yl)but-1-ynv1)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(3-chlorophenyl)-1,2,4-oxadiazole (344 mg, 1.5 mmol) afforded 281 mg of 2-(4-(3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1 ynyl)pyridine (Yield: 61%) as brown oil. LCMS (RT) : 3.94min; MS (ES+) gave m/z : 310.1 1 NMR (CDC1 3 ), 6 (ppm) : 8.56 (d, H), 8.10 (t, H), 7.98 (d, H), 7.63 (t, H), 7.48 (d, H), 7.44-7.36 (m, 2H), 7.22 (in, H), 3.32 (t, 2H), 3.06 (t, 2H). Example 47 2-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-v1)but-l-vnv1)pyridine 47(A) 4-Chloro-N'-hydroxvbcnzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 4-chlorobenzonitrile (0.96 g, 7 mmol) afforded 1.17 g of 4 chloro-N'-hydroxybenzamidine (Yield: 98%) as beige powder (M.P. = 133-134'C). 47(B) 5-(But-3-Yny1)-3-(4-chlorophenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 4-chloro-N'-hydroxybenzamidine (614 mg, 3.6 mmol) afforded 329 mg of 5-(but-3-ynyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole (Yield: 39%) as yellow oil. LCMS (RT) : 4.13min; MS (ES+) gave m/z: 233.0 47(C) 2-(4-(3-(4-Chloropheny1)-1,2.4-oxadiazol-5-vl)but-1-yny1)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole (329 mg, 1.4 nmol) afforded 227 mg of 2-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)but-1 ynyl)pyridine (Yield: 52%) as white solid (M.P. = 75-77'C). LCMS (RT) : 3.93min; MS (ES+) gave m/z: 310 'NMR (CDC1 3 ), 5 (ppm) : 8.56 (d, H), 8.06-8.02 (in, 2H), 7.63 (t, H), 7.49-7.45 (in, 2H), 7.38 (d, H), 7.22 (in, H), 3.31 (t, 2H), 3.06 (t, 2H). Example 48 2-(4-(3-(2,6-Dimethv1phenyl)-1,2,4-oxadiazol-5-yl)but-1-Ynyl)pyridine 48(A) N'-Hydroxy-2,6-dimethvlbenzamnidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2,6-dimethylbenzonitrile (0.92 g, 7 mmol) afforded 0.95 g of N'-hydroxy-2,6-dimethylbenzamidine (Yield : 83%) as beige powder (M.P. = 77 79*C). 48(B) 5-(But-3-ynyl)-3-(2,6-dimethv phenv11-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-2,6-dimethylbenzamidine (591 mg, 3.6 mmol) afforded 485 rug of 5-(but-3-ynyl)-3-(2,6-dimethylphenyl)-1,2,4-oxadiazole (Yield 60%) as yellow oil. LCMS (RT) : 3.88min; MS (ES+) gave m/z : 227.1 WO 2005/123703 PCT/IB2005/002390 115 48(C) 2-(4-(3-(2,6-Dimethv~phenl)-1,2,4-oxadiazol-5-yl)but-1-yny13pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2,6-dimethylphenyl)-1,2,4-oxadiazole (485 mg, 2.1 mmol) afforded 71 mg of 2-(4-(3-(2,6-dimethylpheny)-1,2,4-oxadiazol-5 yl)but-1 -ynyl)pyridine (Yield: 11%) as a brown oil. LCMS (RT) : 3.61min; MS (ES+) gave m/z: 304.1 'NMR (CDC1 3 ), 5 (ppm) : 8.56 (d, H), 7.63 (t, H), 7.48 (d, H), 7.29-7.22 (m, 2H), 7.12-7.08 (d, 2H), 3.35 (t, 2H), 3.07 (t, 2H). Example 49 2-(4-(3-(2-Trifluoromefhvphenvl)-1,2,4-oxadiazol-5-vl)but-l-vnv1)pyridine 49(A) 2-(Trifluoromethyl)-N'-hydroxybenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-(trifluoromethyl)benzonitrile (1.2 g, 7 mmol) afforded 1.4 g of 2-(trifluoromethyl)-N'-hydroxybenzamidine (Yield: 99%) as white powder (M.P. = 74-76-C). 49(B) 5-(But-3-vnv1)-3-(2-(trifluoromethyl)phenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 2-(trifluoromethyl)-N'-hydroxybenzamidine (735 mg, 3.6 mmol) afforded 126 mg of 5-(but-3-ynyl)-3-(2-(trifluoromethyl)phenyl)-1,2,4 oxadiazole (Yield: 13%) as yellow oil. LCMS (RT) : 3.89min; MS (ES+) gave m/z: 267.0 49(C) 2-(4-(3-(2-Trifluoromethyl)phenv1-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2-(trifluoromethyl)phenyl)-1,2,4 oxadiazole (126 mg, 0.5 mmol) afforded 66 mg of 2-(4-(3-(2-trifluoromethy)phenyl) 1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 39%) as a brown oil. LCMS (RT) : 3.61min; MS (ES+) gave m/z: 344.1 ]NMR (CDC13), 5 (ppm) : 8.56 (d, H), 7.87-7.78 (m, 2H), 7.68-7.62 (m, 3H), 7.38 (d, H), 7.22 (m, H), 3.35 (t, 2H), 3.07 (t, 2H). Example 50 2-(4-(3-(Naphthalen-1-yl)-1,2,4-oxadiazol-5-y)but- 1 -vnylpridine 50(A) N'-Hydroxy-1-naphthamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 1-naphthonitrile (1.07 g, 7 mmol) afforded 1.28 g of N' hydroxy-1-naphthamidine (Yield : 98%) as white powder (M.P. = 128-130 C). 50(B) 5-(But-3-ynyl)-3-(naphthalen-1-yl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-l-naphthanidine (670 mg, 3.6 mmol) afforded 264 mg of 5-(but-3-ynyl)-3-(naphthalen-1-y)-1,2,4-oxadiazole (Yield : 30%) as yellow oil. LCMS (RT) : 4.24min; MS (ES+) gave m/z : 249.1 WO 2005/123703 PCT/IB2005/002390 116 50(C) 2-(4-(3-(Naphthalen-1-v1)-1,2,4-oxadiazol-5-vl)but-1-Yny1)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(naphthalen-1-yl)-1,2,4-oxadiazole (264 mg, 1.1 mmol) afforded 105 mg of 2-(4-(3-(naphthalen-1-yl)-1,2,4-oxadiazol-5 yl)but-l-ynyl)pyridine (Yield : 29%) as a brown oil. LCMS (RT) : 4.03min; MS (ES+) gave m/z : 326.1 NMR (CDC1 3 ), 6 (ppm) : 8.91 (d, H), 8.56 (d, H), 8.26 (d, H), 8.02 (d, H), 7.93 (d, H), 7.66-7.56 (m, 4H), 7.40 (d, H), 7.22 (m, H), 3.39 (t, 2H), 3.13 (t, 2H). Example 51 2-(4-(3-(Naphthalen-2-yl)-1,2,4-oxadiazol-5-vl)but-1-vnvl)pvridine 51(A) N'-Hydroxv-2-naphthamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-naphthonitrile (1.07 g, 7 mmol) afforded 1.27 g of N' hydroxy-2-naphthamidine (Yield: 98%) as white powder (M.P. = 147-149'C). 51(B) 5-(But-3-ynvl)-3-(naphthalen-2-yl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-2-naphthamidine (670 mg, 3.6 mmol) afforded 436 mg of 5-(but-3-ynyl)-3-(naphthalen-2-yl)-1,2,4-oxadiazole (Yield : 49%) as yellow oil. LCMS (RT) : 4.29min; MS (ES+) gave m/z: 249.0 51(C) 2-(4-(3-(Naphthalen-2-vl)-1,2,4-oxadiazol-5-vl)but-1-ynvl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(naphthalen-2-yl)-1,2,4-oxadiazole (436 mg, 1.8 mmol) afforded 152 mg of 2-(4-(3-(naphthalen-2-yl)-1,2,4-oxadiazol-5 yl)but-1-ynyl)pyridine (Yield: 26%) as white solid (M.P. = 76-781C). LCMS (RT) : 4.1 min; MS (ES+) gave m/z : 326.1 'NMR (CDCl 3 ), 8 (ppm) : 8.64 (s, H), 8.54 (d, H), 8.15 (d, H), 7.99-7.93 (m, 2H), 7.90 (d, H), 7.65-7.60 (m, H), 7.58-7.53 (m, 2H), 7.40 (d, H), 7.22 (i, H), 3.36 (t, 2H), 3.11 (t, 2H). Example 52 2-(4-(3-(2,3-Dimethvlphenyl)-1,2,4-oxadiazol-5-v1)but-l-vny1)pyridine 52(A) N'-Hydroxy-2,3-dimethylbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of (2,3-dimethylbenzonitrile (0.92 g, 7 mmol) afforded 1.12 g of N'-hydroxy-2,3-dimethylbenzaiidine (Yield: 97%) as white powder (M.P. = 110 111 0 C). 52(B) 5-(But-3-ynyl)-3-(2,3-dimethyphenv1)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-2,3-dimethylbenzamidine (558 mg, 3.4 mmol) afforded 345 mg of 5-(but-3-ynyl)-3-(2,3-dimethylphenyl)-1,2,4-oxadiazole (Yield 45%) as yellow oil.
WO 2005/123703 PCT/IB2005/002390 117 LCMS (RT) : 4.0 1min; MS (ES+) gave m/z : 227.1 52(C) 2-(4-(3-(2,3-Dimethylphenyi)-1,2,4-oxadiazol-5-yl)but-1- 1)nvlpridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2,3-dimethylphenyl)-1,2,4-oxadiazole (345 mg, 1.5 mmol) afforded 175 mg of 2-(4-(3-(2,3-dimethylphenyl)-1,2,4-oxadiazol-5 yl)but-1-ynyl)pyridine (Yield : 38%) as brown oil. LCMS (RT) : 3.81min; MS (ES+) gave m/z: 304.1 1 NMR (CDC1 3 ), 5 (ppm) : 8.64 (s, H), 7.70-7.61 (m, 2H), 7.40 (d, H), 7.32-7.18 (m, 3H), 3.33 (t, 2H), 3.07 (t, 2H), 2.47 (s, 3H), 2.37 (s, 3H). Example 53 . 2-(4-(3-(2.5-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-vnyl)pyridine 53(A) 2,5-Dichloro-N'-hydroxybenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2,5-dichlorobenzonitrile (1.21 mmnol) afforded 1.35 g of 2,5 dichloro-N'-hydroxybenzamidine (Yield: 94%) as yellow oil. 53(B) 5-(But-3-ynyl)-3-(2,5-dichlorophenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 2,5-dichloro-N'-hydroxybenzamidine (697 mg, 3.4 mmol) afforded 425 mg of 5-(but-3-ynyl)-3-(2,5-dichlorophenyl)-1,2,4-oxadiazole (Yield 47%) as yellow oil. LCMS (RT) : 4.21min; MS (ES+) gave m/z : 267.0 53(C) 2-(4-(3-(2,5-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynvllpyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2,5-dichlorophenyl)-1,2,4-oxadiazole (425 mg, 1.6 mmol) afforded 34 2mg of 2-(4-(3-(2,5-dichlorophenyl)-1,2,4-oxadiazol-5 yl)but- 1 -ynyl)pyridine (Yield: 65%) as brown semi-solid. LCMS (RT) : 4.06min; MS (ES+) gave m/z : 346.1 1 NMR (CDC1 3 ), S (ppm) : 8.64 (s, H), 7.97 (d, H), 7.63 (t, H), 7.48 (d, H), 7.43-7.37 (m, 2H), 7.22 (t, H), 3.35 (t, 2H), 3.07 (t, 2H). Example 54 2-(4-(3-(2,5-Dimethylphenyl)-1,2,4-oxadiazol-5-vl)but-1-vnvl)pyridine 54(A) N'-Hydroxy-2,5-dimethylbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2,5-dimethylbenzonitrile (0.92 g, 7 mmol) afforded 1.14 g of N'-hydroxy-2,5-dimethylbenzamidine (Yield: 99%) as yellow oil. 54(B) 5-(But-3-vnyl)-3-(2,5-dimethvlphenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-2,5-dimethylbenzamidine (558 mg, 3.4 mmol) afforded 329 mg of 5-(but-3-ynyl)-3-(2,5-dimethylphenyl)-1,2,4-oxadiazole (Yield 43%) as yellow oil.
WO 2005/123703 PCT/IB2005/002390 118 LCMS (RT): 4.18min; MS (ES+) gave m/z : 227.1 54(C) 2-(4-(3-(2,5-Dimethvlphenyl- 1,2,4-oxadiazol-5-v1)but-1-ynv1)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of (329 mg, 1.5 mmol) of 5-(but-3-yny)-3-(2,5 dimethylphenyl)-1,2,4-oxadiazole afforded 58 mg of 2-(4-(3-(2,5-dimethylphenyl) 1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 13%) as brown oil. LCMS (RT) : 3.98min; MS (ES+) gave n/z : 304.1 NMR (CDC1 3 ), 5 (ppm) : 8.64 (s, H), 7.80(s, H), 7.65 (t, H), 7.40 (d, H), 7.25-7.18 (m, 3H), 3.32 (t, 2H), 3.08 (t, 2H), 2.58 (s, 3H), 2.38 (s, 3H). Example 55 2-(4-(3-(2,6-Dichlorophenyl)-1,2,4-oxadiazol-5-Y1)but-l-ynyl)pyridine 55(A) 2,6-Dichloro-N'-hydroxvbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2,6-dicblorobenzonitrile (1.20 g, 7 mmol) afforded 1.09 g of 2,6-dichloro-N'-hydroxybenzamidine (Yield : 76%) as beige powder (M.P. = 163 164-C). 55(B) 5-(But-3-ynyl)-3-(2,6-dichlorophenvl)-L,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 2,6-dichloro-N'-hydroxybenzamidine (697 mg, 3.4 mmol) afforded 480 mg of 5-(but-3-ynyl)-3-(2,6-dichlorophenyl)-1,2,4-oxadiazole (Yield 53%) as yellow oil. LCMS (RT) : 3.89min; MS (ES+) gave m/z : 267.0 55(C) 2-(4-(3-(2,6-Dichlorophenvl)-1,2,4-oxadiazol-5-yl)but-1-vnyn)pvridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2,6-dichlorophenyl)-1,2,4-oxadiazole (480 mg, 1.8 mmol) afforded 365 mg of 2-(4-(3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5 yl)but-l-ynyl)pyridine (Yield: 59%) as brown oil. LCMS (RT) : 3.73min; MS (ES+) gave m/z : 344.1 1 INMR (CDCl 3 ), 5 (ppm) : 8.64 (s, H), 7.63 (t, H), 7.45-7.36 (m, 4H), 7.22 (t, H), 3.38 (t, 2H), 3.08 (t, 2H). Example 56 2-(4-(3-(2,3-Dichlorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 56(A) 2,3-Dichloro-N'-hydroxvbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2,3-dichlorobenzonitrile (1.20 g, 7 mmol) afforded 1.36 g of 2,3-dichloro-N'-hydroxybenzamidine (Yield : 95%) as beige powder (M.P. = 115 117-C). 56(B) 5-(But-3-ynyl)-3-(2,3-dichlorophenv13)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 2,3-dichloro-N'-hydroxybenzamidine (697 mg, 3.4 mmol) WO 2005/123703 PCT/IB2005/002390 119 afforded 374 mg of 5-(but-3-ynyl)-3-(2,3-dichlorophenyl)-l,2,4-oxadiazole (Yield 41%) as yellow oil. LCMS (RT) : 4.09min; MS (ES+) gave m/z : 267.0 56(C) 2-(4-(3-(2,3-Dichlorophenyl)-1,2,4-oxadiazol-5-Y1)but-1-ynvl)pvridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2,3-dichlorophenyl)-1,2,4-oxadiazole (374 mg, 1.4 mmol) afforded 193 mg of 2-(4-(3-(2,3-dichlorophenyl)-1,2,4-oxadiazol-5 yl)but-l-ynyl)pyridine (Yield: 40%) as brown oil. LCMS (RT): 3.91min; MS (ES+) gave m/z: 346.1 'NMR (CDCl 3 ), 5 (ppm) : 8.64 (s, H), 7.81 (d, 11), 7.66-7.61 (m, 2H), 7.38 (d, H), 7.34 (t, H), 7.22 (t, H), 3.35 (t, 2H), 3.07 (t, 2H). Example 57 2-(4-(3-(2,4-Dichlorophenvl)-L,2,4-oxadiazol-5-yl)but-1-vny1)pyridine 57(A) 2,4-Dichloro-N'-hydroxybenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2,4-dichlorobenzonitrile (1.20 g, 7 mmol) afforded 1.40g of 2,4-dichloro-N'-hydroxybenzamidine (Yield : 98%) as beige powder (M.P. = 149 151-C). 57(B) 5-(But-3-ynyl)-3-(2.4-dichlorophenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 2,4-dichloro-N'-hydroxybenzamidine (697 mg, 3.4 mmol) afforded 553 mg of 5-(but-3-ynyl)-3-(2,4-dichlorophenyl)-1,2,4-oxadiazole (Yield 61%) as yellow oil. LCMS (RT) : 4.21min; MS (ES+) gave m/z: 267.0 57(C) 2 -(4-(3-(2,4-Dichlorophenvl)-1,2,4-oxadiazol-5-vl)but-1-vnvl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2,4-dichlorophenyl)-1,2,4-oxadiazole (553 mg, 2.1 mmol) afforded 430 mg of 2 -(4-(3-(2,4-dichlorophenyl)-1,2,4-oxadiazol-5 yl)but-1-ynyl)pyridine (Yield: 59%) as beige powder (M.P. = 77-78'C). LCMS (RT) : 4.04min; MS (ES+) gave m/z: 344.0 'NMR (CDCl 3 ), 6 (ppm) : 8.64 (s, H), 7.92 (d, H), 7.65 (t, H), 7.57 (d, H), 7.41-7.37 (m, 2H), 7.23 (t, H), 3.34 (t, 2H), 3.06 (t, 2H). Example 58 2-(4-(3-(2-C hloro-6-methylphenvl)-1,2,4-oxadiazol-5-vl)but-1 -yny)pyridine 58(A) 2-Chloro-N'-hydroxy-6-methylbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-chloro-6-methylbenzonitrile (1.06 g, 7 mmol) afforded 1.28 g of 2-chloro-N'-hydroxy-6-methylbenzamidine (Yield : 99%) as beige powder (M.P. = 136-137-C).
WO 2005/123703 PCT/IB2005/002390 120 58(B) 5-(But-3-ynyl)-3-(2-chloro-6-methvlphenv1)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 2-chloro-N'-hydroxy-6-methylbenzamnidine (628 mg, 3.4 mmol) afforded 458 mg of 5-(but-3-ynyl)-3-(2-chloro-6-methylphenyl)-1,2,4 oxadiazole (Yield: 55%) as yellow oil. LCMS (RT) : 3.84min; MS (ES+) gave m/z : no ionisation 58(C) 2-(4-(3-(2-Chloro-6-methyphenv1)- 1,2,4-oxadiazol-5-yl)but- 1 -vnlpyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2-chloro-6-methylphenyl)-1,2,4-oxadiazole (458 mg, 1.9 mmol) afforded 420 mg of 2-(4-(3-(2-chloro-6-methylphenyl)-1,2,4 oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 68%) as brown oil. LCMS (RT) : 3.66min; MS (ES+) gave m/z: 324.1 'NMR (CDC1 3 ), S (ppm) : 8.64 (s, H), 7.63 (t, H), 7.37 (d, H), 7.35-7.30 (m, 2H), 7.24-7.18 (in, 2H), 3.36 (t, 2H), 3.08 (t, 2H), 2.22 (s, 3H). Example 59 2-(4-(3-(5-Fluoro-2-methylphenvl)-.1,2,4-oxadiazol-5-v1)but-1-vnvl)pyridine 59(A) 5-Fluoro-N'-hydroxy-2-methylbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 5-fluoro-2-methylbenzonitrile (0.95g, 7 mmol) afforded 1.27 g of 5-fluoro-N'-hydroxy-2-methylbenzamidine (Yield: 98%) as yellow oil. 59(B) 5-(But-3-ynyl)-3-(5-fluoro-2-methylphenv1)-1,2,-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 5-fluoro-N'-hydroxy-2-methylbenzamidine (572 mg, 3.4 mmol) afforded 325 mg of 5-(but-3-ynyl)-3-(5-fluoro-2-methylphenyl)-1,2,4 oxadiazole (Yield: 42%) as yellow oil. LCMS (RT) : 4.06min; MS (ES+) gave m/z : 231.1 59(C) 2-(4-(3-(5-Fluoro-2-methylphenvl)-1,2,4-oxadiazol-5-vl)but-1-ynyl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(5-fluoro-2-methylphenyl)-1,2,4-oxadiazole (325 mg, 1.4 mmol) afforded 190 mg of 2-(4-(3-(5-fluoro-2-methylphenyl)-1,2,4 oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 44%) as beige powder (M.P. = 90-91'C). LCMS (RT) : 3.91min; MS (ES+) gave m/z: 308.0 'NMR (CDC1 3 ), S (ppm) : 8.64 (s, H), 7.63 (t, H), 7.37 (d, H), 7.34-7.29 (m, 2H), 7.24-7.18 (m, 2H), 3.36 (t, 2H), 3.08 (t, 2H), 2.22 (s, 3H). Example 60 2-(4-(3-(5-Chloro-2-methvlphenl)-1,2,4-oxadiazol-5-vl)but-l-ynyl)pyridine 60(A) 5-Chloro-N'-hydroxy-2-methylbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 5-chloro-2-methylbenzonitrile (1.06g, 7 mmol) afforded 1.27 g of 5-chloro-N'-hydroxy-2-methylbenzamnidine (Yield: 98%) as beige powder (M.P. = 111-113-C).
WO 2005/123703 PCT/IB2005/002390 121 60(B) 5-(But-3-yny1)-3-(5-chloro-2-methvlphenyl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 5-chloro-N'-hydroxy-2-methylbenzanidine (628 mg, 3.4 mmol) afforded 376 mg of 5-(but-3-ynyl)-3-(5-chloro-2-methylphenyl)-1,2,4 oxadiazole (Yield: 45%) as yellow oil. LCMS (RT) : 4.34min; MS (ES+) gave m/z: 247.1 60(C) 2-(4-(3-(5-Chloro-2-methvlphenvl)-I.,2,4-oxadiazol-5-vl)but-1-vnvl)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(5-chloro-2-methylphenyl)-1,2,4-oxadiazole (376 mg, 1.5 mmol) afforded 310 mg of 2-(4-(3-(5-chloro-2-methylphenyl)-1,2,4 oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 64%) as beige powder (M.P. = 66-68'C). LCMS (RT) : 4.16min; MS (ES+) gave m/z : 324.1 lNMR (CDC1 3 ), 6 (ppm) : 8.64 (s, H), 8.02 (d, H), 7.63 (t, H), 7.40 (d, H), 7.35 (d, H), 7.28-7.21 (m, 2H), 3.33 (t, 2H), 3.07 (t, 2H), 2.60 (s, 3H). Example 61 2-(4-(3-(2-(Trifluoromethoxy3hhenv1)-1,2,4-oxadiazol-5-vl)but-1-ynyl)pyridine 61(A) N'-Hydroxy-2-(trifluoromethoxy)benzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 2-(trifluoromethoxy)benzonitrile (1.31 g, 7 mmol) afforded 1.55 g of N'-hydroxy-2-(trifluoromethoxy)benzamidine (Yield : 96%) as beige powder (M.P. = 95-97*C). 61(B) 5-(But-3-vnyl)-3-(2-(tifluoromethoxy)phenl) -1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of N'-hydroxy-2-(trifluoromethoxy)benzamidine (749 mg, 3.4 mmol) afforded 303 mg of 5-(but-3-ynyl)-3-(2-(trifluoromethoxy)phenyl)-1,2,4 oxadiazole (Yield: 32%) as yellow oil. LCMS (RT) : 4.03min; MS (ES+) gave m/z : 263.1 61(C) 2-(4-(3-(2-(Trifluoromethoxv)phenl)-1,2,4-oxadiazol-5-yl)but-1 vnvllpyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(2-(trifluoromethoxy)phenyl)-1,2,4 oxadiazole (303 mg, 1.1 mmol) afforded 213 mg of 2-(4-(3-(2 (trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield : 54%) as brown oil. LCMS (RT) : 3.84min; MS (ES+) gave m/z: 360.1 lNMR (CDCl 3 ), 6 (ppm) : 8.64 (s, H), 8.11 (d, H), 7.63 (t, H), 7.56 (t, H), 7.48-7.42 (m, 2H), 7.37 (d, H), 7.23 (t, H), 3.33 (t, 2H), 3.07 (t, 2H). Example 62 6-Fluoro-2-(4-(pyridin-2-vl)but-3-vnvl)benzofdloxazole 62(A) 2-Amino-5-fluorophenol WO 2005/123703 PCT/IB2005/002390 122 A suspension of 3-fluoro-6-nitrophenol (500 mg, 3.18 mmol) and zinc (2.10 g, 31.8 mmol) in acetic acid (7.3 mL) was stirred overnight at room temperature. The reaction mixture was filtered through celite and washed with DCM. After evaporation and distillation under vacuum (2.102 mbar) of the solvents, the residue was dissolved in DCM. The organic phase was washed with a saturated solution of NaHCO 3 and brine, dried over MgS04, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5) to yield 177 mg (1.39 mmol, 44%) of 2 amino-5-fluorophenol as an orange solid. 62(B) 2-(But-3-ynyl)-6-fluorobenzordloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-5-fluorophenol (177 mg, 1.39 mmol). Reaction time: 3 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 47 mg (0.25 mamol, 18%) of 2 -(but-3-ynyl)-6-fluorobenzo[d]oxazole. 62(C) 6-Fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzofdloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (39 mg, 0.25 mmol) and 2-(but-3-ynyl)-6 fluorobenzo[d]oxazole (47 mg, 0.25 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 21 mg (78 pmol, 31%) of 6-fluoro-(2 (4-pyridin-2-yl)but-3 -ynyl)benzo[d]oxazole as a brown solid. LCMS (RT) : 3.04min; MS (ES+) gave m/z : 267.0. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.05 (t, J=7.5, 211), 3.28 (t, J=7.5, 2H), 7.04-7.09 (m, 1H), 7.18-7.22 (m, 1H), 7.23 (dd, J=2.5 and 8.0, 1H), 7.35 (d, J=2.5, 1H), 7.59-7.63 (2H), 8.53-8.56 (m, 1H). Example 63 7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzordloxazole 63(A) 2-Amino-6-chlorophenol The title compound was prepared in accordance with the general method of Example 62(A), from 6-chloro-2-nitrophenol (500 mg, 2.88 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5) to yield 73 mg (0.51 mmol, 18%) of 2-amino-6-chlorophenol. 63(B) 2-(But-3-ynyl)-7-chlorobenzofdloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-chlorophenol (73 mg, 0.51 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 42 mg (0.20 mmol, 40%) of 2-(but-3-ynyl)-7-chlorobenzo[d]oxazole. 63(C) 7-Chloro-2-(4-(pyridin-2-yl)but-3-yny1)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (32 mg, 0.20 mmol) and 2-(but-3-ynyl)-7 chlorobenzo[d]oxazole (42 mg, 0.20 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 25 mg (90 pmol, 44%) of 7-chloro-2-(4 (pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil. LCMS (RT) : 3.44min; MS (ES+) gave m/z: 283.0, 285.0.
WO 2005/123703 PCT/IB2005/002390 123 'H-NMR (CDCl 3 ), 6 (ppm) : 3.08 (t, 1=8.0, 2H), 3.33 (t, J=8.0, 2H), 7.18-7.21 (m, 1H), 7.24-7.28 (m, 1H), 7.32 (dd, J=1.0 and 8.0, 1H), 7.36-7.39 (m, 1H), 7.57-7.63 (2H), 8.53-8.55 (m, 1H). Example 64 7-Fluoro-2-(4-(pyridin-2-vl)but-3-vnvl)benzoFdloxazole 64(A) 2-Amino-6-fluorophenol The title compound was prepared in accordance with the general method of Example 62(A), from 6-fluoro-2-nitrophenol (500 mg, 3.18 mmol). The crude residue was purified by flash chromatography (AcOEt/cyclohexane 7:3) to yield 213 mg (1.68 mmol, 54%) of 2-amino-6-fluorophenol as a brown solid. 64(B) 2-(But-3-vnyl)-7-fluorobenzo[dloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-fluorophenol (213 mg, 1.68 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 128 mg (0.68 mmol, 40%) of 2-(but-3-ynyl)-7-fluorobenzo[d]oxazole. 64(C) 7-Fluoro-2-(4-(pyridin-2-vl)but-3-ynvl)benzo dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (107 mg, 0.68 mol) and 2-(but-3-ynyl)-7 fluorobenzo[d]oxazole (128 mg, 0.68 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 94 mg (0.35 nnnol, 52%) of 7-fluoro-2 (4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil. LCMS (RT) : 3.13min; MS (ES+) gave m/z: 267.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.08 (t, J=7.0, 2H), 3.32 (t, J=7.0, 2H), 7.05-7.10 (m, 1H), 7.18-7.21 (m, 1f), 7.23-7.28 (m, 1H), 7.36-7.38 (m, 1K), 7.48 (dd, J=1.0 and 8.0, 1H), 7.59-7.63 (m, 1H), 8.53-8.55 (m, 1H). Example 65 2-(4-(5-Phenvloxazol-2-yl)but-1-vn1)pylridine 65(A) N-(2-Hydroxy-2-phenvlethl)pent-4-vnamide To a solution of pent-4-ynoic acid (1.00 g, 10.2 mmol) in dry DCM (10 mL) was added at room temperature oxalyl chloride (1.75 mL, 20.0 mmol) and some drops of DMF. The reaction mixture was stirred for 2 hoursand was concentrated to dryness to yield pent-4-ynoyl chloride which was used without further purification. A solution of 390 mg (3.35 mmol) of pent-4-ynoyl chloride in dry DCM (5 mL) was added slowly to a solution of 2-amino-1-phenylethanol (480 mg, 3.30 mmol) and triethylamine (0.93 mL, 6.69 mmol) in dry DCM (10 mL). The reaction mixture was stirred for 20 min. at room temperature. After evaporation of the solvent, the crude product was dissolved in DCM. The organic phase was washed with a saturated solution of NaHCO 3 , brine, dried over MgSO4, filtered and concentrated to lead in a quantitative yield to 727 mg (3.35 mmol) of N-(2-hydroxy-2-phenylethyl)pent-4-ynamide.
WO 2005/123703 PCT/IB2005/002390 124 65(B) Pent-4-ynoic acid (2-oxo-2-phenyl-ethyl)-amide 169 mg (0.78 mmol) of N-(2-hydroxy-2-phenylethyl)pent-4-ynamide in DCM (1 mL) were added to a solution of PCC (326 mg, 1.48 mmol) in DCM (4 mL). The reaction mixture was stirred for 4 hours at room temperature, dissolved in DCM and then quenched with NaOH 1N. The organic phase was washed with brine, dried over MgSO 4 , filtered and concentrated to yield 160 mg (0.74 mmol, 95%) of pent-4-ynoic acid (2-oxo-2-phenyl-ethyl)-amide as a yellow solid. 65(C) 2-(But-3-vnyl)-5-phenyloxazole 907 mg (6.39 mmol) of P205 were added to a solution of pent-4-ynoic acid (2-oxo-2 phenyl-ethyl)-amide (160 mg, 0.74 mmol) in POCl 3 (10.4 mL). The reaction mixture was stirred for 2 hours at 105'C and then poured carefully onto ice. The solution was basified with NaOH 1N followed by NaOH pellets till pH=8. The aqueous phase was extracted thrice with DCM. The organic phase was washed with brine, dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 31 mg (0.16 mmol, 21%) of 2-(but-3 ynyl)-5-phenyloxazole as an orange oil. 65(D) 2-(4-(5-Phenyloxazol-2-yl)but-1-vnvl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (25 mg, 0.16 mmol) and 2-(but-3-ynyl)-5-phenyloxazole (31 mg, 0.16 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 95:5, DCM/MeOH/NH 4 0H 90:5:0.1 to 90:9:1) to yield 4.0 mg (15 vmol, 9%) of 2-(4-(5-phenyloxazol-2-yl)but-l ynyl)pyridine as a yellow oil. LCMS (RT) : 3.33min; MS (ES+) gave m/z: 275.1. Example 66 2-(4-(3-(3-Chloro-2-methvlphenvl)-1,2,4-oxadiazol-5-Vl)but-1-vnvl)pyridine 66(A) 3-Chloro-N'-hydroxy-2-methylbenzamidine According to the general protocol for amidoxime synthesis described in Example 15(A), the conversion of 3-chloro-2-methylbenzonitrile (1.06 g, 7 mmol) afforded 1.28 g of 3-chloro-N'-hydroxy-2-methylbenzamidine (Yield : 99%) as beige powder (M.P. = 119-121-C). 66(B) 5-(But-3-vnyl)-3-(3-chloro-2-methylphenvl)-1,2,4-oxadiazole According to the general protocol for oxadiazole synthesis described in Example 40(B), the conversion of 3-chloro-N'-hydroxy-2-methylbenzamidine (628 mg, 3.4 mmol) afforded 387 mg of 5-(but-3-ynyl)-3-(3-chloro-2-methylphenyl)-1,2,4 oxadiazole (Yield: 46%) as yellow oil. LCMS (RT) : 4.26min; MS (ES+) gave m/z : 247.1 66(C) 2-(4-(3-(3-Chloro-2-methylphenyl)-l.2,4-oxadiazol-5-yl)but-1-vnv1)pyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 5-(but-3-ynyl)-3-(3-chloro-2-methylphenyl)-1,2,4-oxadiazole (628 mg, 3.4 mmol) afforded 387 mg of 2-(4-(3-(3-chloro-2-methylphenyl)-1,2,4 oxadiazol-5-yl)but-1-ynyl)pyridine (Yield 46%) as brown oil. LCMS (RT) : 4.08min; MS (ES+) gave m/z : 324.1 WO 2005/123703 PCT/IB2005/002390 125 'N4R (CDCl 3 ), 8 (ppm): 8.64 (s, H), 7.79 (d, H), 7.64 (t, H), 7.52 (d, H), 7.38 (d, H), 7.28-7.20 (m, 2H), 3.34 (t, 2H), 3.07 (t, 2H), 2.64 (s, 3H). Example 67 8-Methyl-2-(4-(pyridin-2-v)but-3-ynl)-imidazof1,2-alpyridine 67(A) Ethyl 8-methyl-imidazoF, 2 -alpyridine-2-carboxylate According to the general protocol as described in Example 33(A), the conversion of 3-methylpyridin-2-amine (2.3 g, 21 mmol) afforded 2.97 g of ethyl 8-methyl inidazo[1,2-a]pyridine-2-carboxylate (Yield : 69%) as a red solid. Purification over silicagel chromatography (DCM/MeOH from 100/0 to 97/3 as eluent). LCMS (RT) : 0.72-1.77min; MS (ES+) gave m/z: 205.1 Rf (DCM/MeOH: 98/2): 0.22 67(B) (8-Methyl-imidazoF1, 2 -alpyridin-2-vlmehanol According to the general protocol as described in Example 33(B), the conversion of ethyl 8-methyl-imidazo[1,2-a]pyridine-2-carboxylate (2.97 g, 14.5 mmol) afforded 1.17 g of (8-methyl-imidazo[1, 2 -a]pyridin-2-yl)methanol (Yield : 50%) as a orange oil. Purification over silicagel chromatography (prepacked 7 Og silicagel column, DCM/MeOH from 100/0 to 95/5 as eluent). LCMS (RT) : 0.67min; MS (ES+) gave m/z : 163.1 Rf (DCM/MeOH: 95/5): 0.10 67(C) 2 -(Chloromethyl)-8-methyl-imidazo[1,2-alpyridine According to the general protocol as described in Example 33(C), the conversion of (8-methyl-imidazo[1,2-a]pyridin-2-yl)methanol (1.17 g, 7.21 mmol) afforded 1.23 g of 2-(chloromethyl)-8-methyl-imidazo[1,2-a]pyridine (Yield : 94%) as a brownish solid (M.P.: 115.4-116.8'C). LCMS (RT) : 0.
64 -1.05min; MS (ES+) gave m/z : 18 1.1 Rf (DCM/MeOH : 95/5): 0.27 67(D) 8-Methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazoF1,2-alpyridine To a solution of trimethyl(prop-1-ynyl)silane (259 mg, 2.31 mmol) in TFF (7.5 mL) at -78'C was added n-BuLi 2.5M in hexane (1.1 mL, 2.8 mmol). After 90min at -78'C 2 -(chloromethyl)-8-methyl-imidazo[1,2-a]pyridine (500 mg, 2.8 mmol) in THF (5 mL) was added dropwise. The solution became blue-green at -78'C. The solution was stirred at -78'C for an additional lh. The reaction was quenched with water and the solvent was removed under reduced pressure. The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as fluent) to afford 590 mg of 8-methyl-2-(4-(trimethylsilyl)but-3-ynyl) inidazo[l,2-alpyridine (Yield: 100%) as an yellow oil. LCMS (RT) : 0.59-2.61min; MS (ES+) gave m/z : 257.1 Rf (DCM/MeOH : 95/5) : 0.22 67(E) 2-(But-3-vnvl)-8-methyl-inidazoF1,2-alpvridine According to the protocol described in Example 38(D), the conversion of 8-methyl-2 (4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (590 mg, 2.30 rnmol) afforded 424 mg of 2 -(but- 3 -ynyl)-8-methyl-imidazo[1,2-a]pyridine (Yield : 100%) as yellow WO 2005/123703 PCT/IB2005/002390 126 oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: 95/5 as eluent). LCMS (RT) : 2.89min; MS (ES+) gave m/z: 265.1 67(F) 8-Methyl-2-(4-(pyridin-2-yl)but-3-ynL)-imidazo1 ,2-alpyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 2-(but-3-ynyl)-8-methyl-imidazo[1,2-a]pyridine (100 mg, 0.54 mmol) afforded 114 mg of 8-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2 a]pyridine (Yield: 80%) as yellow oil. Purification over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH.: 97/3 as fluent). LCMS (RT) : 2.16min; MS (ES+) gave m/z : 262.1 Rf (DCM/MeOH : 95/5) : 0.33 'H-NMR (CDC1 3 ), 5 (ppm) : 8.54 (d, H), 7.98 (d, H), 7.62 (t, H), 7.55 (s, H), 7.36 (d, H), 7.18 (m, H), 7.00 (d, H), 6.72 (t, H), 3.20(t, 2H), 2.94 (t, 2H), 2.64 (s, 3H). Example 68 5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-alpyridine 68(A) Ethyl 5-methyl-imidazo[l.2-alpyridine-2-carboxylate According to the general protocol as described in Example 33(A), the conversion of 6-methylpyridin-2-amine (2.3 g, 21 mmol) afforded 2.59 g of ethyl 5-methyl imidazo[1,2-a]pyridine-2-carboxylate (Yield : 60%) as a brownish solid. Purification over silicagel chromatography (DCM/MeOH from 100/0 to 97/3 as eluent). LCMS (RT) : 0.72-1.49min; MS (ES+) gave m/z : 205.1 Rf (DCM/MeOH : 98/2) : 0.22 68(B) (5-Methyl-imidazo[l,2-alpyridin-2-yl)methanol According to the general protocol as described in Example 33(B), the conversion of ethyl 5-methyl-imidazo[1,2-a]pyridine-2-carboxylate (2.59 g, 12.7 mmol) afforded 1.58 g of (5-methyl-imidazo[1,2-a]pyridin-2-yl)methanol (Yield: 77%) as a yellowish solid. Purification over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH from 100/0 to 95/5 as eluent). LCMS (RT) : 0.67min; MS (ES+) gave m/z: 163.1 Rf (DCM/MeOH: 95/5) : 0.32 68(C) 2-(Chloromethyl)-5-methyl-imidazor1,2-alpyridine According to the general protocol as described in Example 33(C), the conversion of (5-methyl-imidazo[1,2-a]pyridin-2-yl)methanol (1.58 g, 9.74 mmol) afforded 1.67 g of 2-(chloromethyl)-5-methyl-imidazo[1,2-a]pyridine (Yield : 95%) as a beige solid (M.P. : 120-120.6'C). LCMS (RT) : 0.64-1.05min; MS (ES+) gave m/z : 181.1 Rf (DCM/MeOH : 95/5) : 0.27 68(D) 5-Methyl-2-(4-(trimethylsilyl)but-3-yny1)-imidazo[1,2-alpyridine According to the general protocol as described in Example 67(D), the conversion of of 2-(chloromethyl)-5-methyl-imidazo[1,2-a]pyridine (500 mg, 2.80 mmol) afforded 525 mg of 5-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield WO 2005/123703 PCT/IB2005/002390 127 89%) as an yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent). LCMS (RT): 0.59-2.59min; MS (ES+) gave m/z : 257.1 Rf (DCM/MeOH: 95/5) : 0.19 68(E) 2-(But-3-ynyl)-5-methyl-imidazo[1,2-alpyridine According to the protocol described in Example 38(D), the conversion of 5-methyl-2 (4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (525 mg, 2.04 mmol) afforded 352 mg of 2-(but-3-ynyl)-5-methyl-inidazo[1,2-a]pyridine (Yield : 93%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: 95/5 as eluent). LCMS (RT) : 2.89min; MS (ES+) gave m/z : 265.1 68(F) 5-Methyl-2-(4-pyridin-2-v13but-3-ynyl)-imidazo[1,2-alpyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 2-(but-3-ynyl)-5-methyl-imidazo[1,2-a]pyridine (100 mg, 0.54 mmol) afforded 78 mg of 5-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2 a]pyridine (Yield : 55%) as yellow oil. Purification over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: 97/3 as eluent). LCMS (RT) : 2.19min; MS (ES+) gave m/z : 262.1 Rf (DCM/MeOH : 95/5) : 0.30 'H-NMR (CDCl 3 ), 6 (ppm) : 8.54 (d, H), 7.61 (t, H), 7.53 (d, H), 7.44 (s, H), 7.37 (d, H), 7.22-7.15 (m, 2H), 6.65 (d, H), 3.20 (t, 2H), 2.95 (t, 2H), 2.59 (s, 3H). Example 69 5-Phenyl-2-(4-(pyridin-2-yl)but-3-vnvl)-imidazo[1,2-alpyridine 69(A) Ethyl 5-bromo-imidazo[1,2-alpyridine-2-carboxylate According to the general protocol as described in Example 33(A), the conversion of 6-bromopyridin-2-amine (3.6 g, 21 mmol) afforded 4.70 g of ethyl 5-bromo imidazo[1,2-a]pyridine-2-carboxylate (Yield : 83%) as a yellow solid. Purification over silicagel chromatography (DCM/MeOH from 100/0 to 97/3 as fluent). LCMS (RT) : 2.87min; MS (ES+) gave m/z: 270.1 Rf (DCM/MeOH : 98/2) : 0.22 69(B) Ethyl 5-phenyl-imidazor1,2-alpyridine-2-carboxylate To a suspension of ethyl 5-bromo-imidazo[1,2-a]pyridine-2-carboxylate (1.50 g, 5.6 mmol) , Pd(PPh 3
)
4 (322 mg, 0.279 mmol) in a mixture of toluene (17 mL), NaHC0 3 1M (6 mL) and MeOH (4 mL) was added phenylboronic acid at room temperature. The resulting reaction mixture was heated at 80'C for 12h, cooled, and diluted with water (50 mL). The insoluble matter was filtered off, and the phases were separated. The aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with water and the solvent was removed under reduced pressure. The crude product was purified by chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent) to afford 1.41 g of ethyl 5-phenyl imidazo[1,2-a]pyridine-2-carboxylate (Yield: 95%) as a yellowish solid (M.P. : 123 123.8-C) LCMS (RT) : 3.06min; MS (ES+) gave m/z : 266.1 Rf (DCM/MeOH: 98/2) : 0.18 WO 2005/123703 PCT/IB2005/002390 128 69(C) (5-Phenyl-imidazol,2-alpyridin-2-vl)methanol According to the general protocol as described in Example 33(B), the conversion of ethyl 5-phenyl-imidazo[1,2-a]pyridine-2-carboxylate (1.40 g, 5.26 mmol) afforded 538 mg of (5-phenyl-imidazo[1,2-a]pyridin-2-yl)methanol (Yield: 45%) as an orange oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 98/2 as eluent). LCMS (RT) : 0.65-1.77min; MS (ES+) gave m/z: 225.1 Rf (DCM/MeOH: 90/10) : 0.28 69(D) 2-(Chloromethyl)-5-phenyl-imidazol,2-alpyridine According to the general protocol as described in Example 33(C), the conversion of (5-phenyl-imidazo[1,2-a]pyridin-2-yl)methanol (538 mg, 2.40 mmol) afforded 555 mg of 2-(chloromethyl)-5-phenyl-imidazo[1,2-apyridine (Yield : 95%) as a beige solid (M.P. : 125.8-126.6'C). LCMS (RT) : 0.65-2.31min; MS (ES+) gave m/z : 243.1 Rf (DCM/MeOH: 90/10) : 0.31 69(E) 2-(4-(Trimethylsilyl)but-3-yny1)-5-pheny1-imidazo[1,2-alpyridine According to the general protocol as described in Example 67(D), the conversion of 2-(chloromethyl)-5-phenyl-inidazo[1,2-a]pyridine (500 mg, 2.10 mmol) afforded 543 mg of 2-(4-(trimethylsilyl)but-3-ynyl)-5-pheny-imidazo[1,2-a]pyridine (Yield: 99%) as an yellow oil Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent). LCMS (RT) : 3.08min; MS (ES+) gave m/z : 319.1 Rf (DCM/MeOH: 95/5) : 0.31 69(F) 2-(But-3-ynyl)-5-phenyl-imidazo[1,2-alpyridine According to the protocol described in Example 38(D), the conversion of 2-(4 (trimethylsilyl)but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine (500 mg, 1.90 mmol) afforded 350 mg of 2-(but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine (Yield : 97%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH : 95/5 as eluent). LCMS (RT) : 2.89min; MS (ES+) gave m/z : 265.1 69(G) 5-Phenyl-2-(4-(pyridin-2-yl)but-3-ny1)-imidazo[1,2-alpyridine According to the general protocol for Sonogashira coupling described in Example 15(C), the conversion of 2-(but-3-ynyl)-5-phenyl-imidazo[1,2-a]pyridine (100 mg, 0.40 mmol) afforded 100 mg of 5-phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2 a]pyridine (Yield : 76%) as yellow oil. Purification over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : 97/3 as eluent). LCMS (RT) : 2.84min; MS (ES+) gave m/z : 324.1 Rf (DCM/MeOH: 95/5) : 0.30 'H-NMR (CDC1 3 ), 8 (ppm) : 8.54 (d, H), 7.61-7.65 (in, 2H), 7.61-7.57 (m, 3H), 7.52 7.48 (m, 3H), 7.32-7.24 (m, 2H), 7.18 (m, H), 6.74 (d, H), 3.12 (t, 2H), 2.90 (t, 2H).
WO 2005/123703 PCT/IB2005/002390 129 Example 70 2-(4-(Pyridin-2-yl)but-3-ynylbenzofdloxazol-4-ol 70(A) 2-Aminobenzene-L,3-diol The title compound was prepared in accordance with the general method of Example 62(A), from 2-nitrobenzene-1,3-diol (1.37 g, 8.81 mmol). 1.10 g (8.81 mmol, 100%) of 2-aminobenzene-1,3-diol were obtained as an orange solid and used without purification. 70(B) 2-(But-3-ynyl)benzold1oxazol-4-ol The title compound was prepared in accordance with the general method of Example 8(A), from 2-aminobenzene-1,3-diol (272 mg, 2.17 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 241 mg (1.29 mmol, 60%) of 2-(but-3-yny)benzo[d]oxazol-4-ol as an orange solid. 70(C) 2-(4-(Pyridin-2-y1)but-3-yny1)benzoFdloxazol-4-ol The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (203 mg, 1.29 mol) and 2-(but-3-yny1)benzo[d]oxazol-4-ol (241 mg, 1.29 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH 4 0H 94:5:1 to 90:8:2) to yield 25 mg (95 imol, 7%) of 2-(4 (pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol as an orange solid. LCMS (RT) : 3.26min; MS (ES+) gave m/z : 265.0. Rf (DCM/MeOH 98:2) = 0.04. Example 71 2-(4-(5-Fluoropyridin-2-vl)but-3-ynvl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoropyridine (200 mg, 1.14 mol) and 2-(but-3 ynyl)benzo[d]oxazole (195 mg, 1.14 mmol, Example 8(A)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH40H 94:5:1 to 90:8:2) to yield 15 mg (56 ptmol, 5%) of 2-(4-(5-fluoropyridin-2-y1)but-3-ynyl)benzo[d]oxazole as a white solid. LCMS (RT) : 4.19min; MS (ES+) gave m/z : 267.0. Example 72 4-Methoxy-2-(4-(pyridin-2-l)but-3-nllbenzofdloxazole A mixture of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[doxazol-4-ol (20 mg, 76 [pmol, Example 70), methyl iodide (57 pL, 114 pmol) and K 2 C0 3 (18 mg, 130 jmol) in DMF (2 mL) was stirred under reflux for 3 h. The reaction mixture was then allowed to cool to room temperature and was dissolved in DCM. The organic phase was washed with water, HCl 1N, saturated solution of NaHCO 3 , brine, dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography WO 2005/123703 PCT/IB2005/002390 130 (DCM/MeOH 99:1) to yield 10 mg (36 [tmol, 47%) of 4-nethoxy-2-(4-(pyridin-2 yl)but-3-ynyl)benzo[d]oxazole as a brown solid. LCMS (RT) : 3.69min; MS (ES+) gave m/z : 279.1. Example 73 2-(4-(2-Methylthiazol-4-vl)but-3-ynyl)imidazo[l,2-alpyridine 73(A) 4-Bromo-2-methylthiazole' To a solution of 2,4-Dibromothiazole (5.00 g, 20.6 mmol) in anhydrous Diethyl ether (70 mL) was added dropwise at -781C, 11 mL of BuLi 2.5M in hexane. The mixture was stirred for 2h at -78'C. A solution of methyl trifluoromethanesulfonate (3.38 g, 20.6 mmol) in 10 mL of Diethyl ether was added dropwise at -78'C to the resulting mixture. After 30 min of stirring at -78 C, the reaction mixture was slowly warmed to room temperature for 2h. The reaction was cooled with a ice bath at -10 0 C and quenched with water. The layers were separated; the aqueous layer was extracted with Diethyl ether. The combined organic layers were dried over Na 2 S04, filtered and concentrated under medium pressure 700 mbar, bath 35'C, because the bromothiazole is very volatil. The crude product was purified by flash chromatography (Prepacked 70 g silicagel column with Pentane/ Diethyl ether : 95/5 as eluent) to afford 2 g of 4 bromo-2-methylthiazole (Yield: 54%) as a yellow oil. Rf (Pentane / Diethyl ether 95/5) : 0.30 LCMS (RT): 3.33min; MS (ES+) gave m/z : 179.0 73(B) 4-Iodo-2-methylthiazole To a solution of 4-bromo-2-methylthiazole (2.0 g, 11 mmol) in anhydrous Diethyl ether (44 mL) was added dropwise at -78'C, 5.30 mL of BuLi 2.5M in hexane. The mixture was stirred for 1h at -78'C. A solution of diiodoethane (6.20 g, 22 mmol) in 27 mL of Diethyl ether was added dropwise at -78'C to the reaction mixture. The resulting solution was stirred 30 min at -78'C and slowly warmed to room temperature over a period of 2h. The reaction cooled with a ice bath at -10 0 C and quenched with water. The two layers were separated; the aqueous layer was extracted with Diethyl ether. The combined organic layers were dried over Na 2
SO
4 , filtered and concentrated under medium pressure. The crude product was purified by flash chromatography (Prepacked 10 g silicagel column with Pentane/ Diethyl ether : 95/5 as eluent) to afford 1.17 g of 4-iodo-2-methylthiazole (Yield: 47%) as a colorless oil. LCMS (RT) : 3.49min; MS (ES+) gave m/z : 225.0 73(C) 2-(4-(2-Methylthiazol-4-vl)but-3-vnl)-imidazo[1,2-alpyridine In a dry reaction tube containing in suspension copper iodide (6.5 mg, 0.03 mmol) and triethylamine (2.33 mL, 13.60 mmol), were added 4-iodo-2-methylthiazole (150 mg, 0.68 mmol) and Pd(PPh 3
)
2 C1 2 (39 ng, 0.03 mmol) under N 2 . A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution 2-(but-3-ynyl1)-imidazo[1,2-a]pyridine (115 mg, 0.68 mmol) in triethylamine(0.5 mL) under N 2 . Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 4h and 50'C overnight under N 2 . Triethylamine was removed under reduce pressure. The crude product was purified by flash chromatography (Prepacked 25 g silicagel column from DCM/MeOH : 100/0 to 97/3 as eluent) to afford 25 mg of 2-(4-(2-methylthiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 14%) as a yellow oil.
WO 2005/123703 PCT/IB2005/002390 131 Rf (DCM / MeOH: 95/5): 0.50 LCMS (RT) : 0.79-2.38min; MS (ES+) gave m/z : 268.0 'H-NMR (CDC1 3 ), 8 (ppm) : 8.09 (d, H), 7.66 (d, H), 7.52 (s, H), 7.23-7.18 (m, 2H), 6.81 (t, H), 3.14 (t, 2H), 2.92 (t, 2H), 2.70 (s, 3H). Example 74 6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-alpyridine 74(A) 2-(Chloromethyl-6-fluoro-imidazo[I,2-alpyridine According to the general protocol described in J.Heterocyclic.Chem., 1988, 25, 129 137, to solution of 5-fluoropyridin-2-amine (1.80 g, 16 mmol) in EtOH (24 mL) was added 1,3-dichloropropan-2-one (2.03 g, 16 mmol) and the resulting mixture was stirred overnight at 80'C. The solvent was evaporated, and the residue was dissolved in a minimum volume of water. The solution was neutralized (pH = 8) with saturated NaHCO 3 . The aqueous layer was extracted with AcOEt and the organic layer was washed with saturated NaCl. The solvent was evaporated and the crude product was purified by chromatography (prepacked 25 g silicagel column, DCM as eluent) to afford 1.7 g of 2-(chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine (Yield : 57%) as a beige solid. LCMS (RT) : 0.88-1.68min; MS (ES+) gave m/z: 185.0 Rf (DCM/MeOH: 98/2) : 0.50 74(B) 6-Fluoro-2-(4-(trimethylsilyl but-3-ynyl)-imidazo[1,2-alpyridine According to the general protocol as described in Example 38(C), the conversion of 2 (chloromethyl)-6-fluoro-imidazo[1,2-a]pyridine (1.70 g, 9.1 mmol) afforded 496 mg of 6-fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 25%) as white powder. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt from 70/30 to 60/40 as eluent). LCMS (RT): 3.01min; MS (ES+) gave m/z : 261.0 Rf (Cyclohexane/AcOEt : 50/50) : 0.50 74(C) 2-(But-3-ny1)-6-fluoro-imidazo[1,2-alpyridine According to the protocol described in Example 38(D), the conversion of 6-fluoro-2 (4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (490 mg, 1.90 mmol) afforded 333 mg of 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (Yield: 93%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH : 98/2 as eluent). LCMS (RT) : 0.79min; MS (ES+) gave m/z : 189.0 Rf (DCM/MeOH: 98/2): 0.30 74(D) 6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynl)-imidazoFl,2-alpyridine According to the general protocol for Sonogashira coupling described in Example 40(C), the conversion of 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (331 mg, 1.76 mmol) afforded 230 mg of 6-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2 a]pyridine (Yield 49%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH : from 100/0 to 97/3 as eluent). LCMS (RT) : 0.79-2.06min; MS (ES+) gave m/z : 266.0 Rf (DCM/MeOH: 95/5): 0.50 WO 2005/123703 PCT/IB2005/002390 132 'H-NMR (CDC1 3 ), 8 (ppm): 8.54 (d, H), 8.01 (m, H), 7.62 (m, H), 7.56-7.51 (in, 2H), 7.37 (d, H), 7.22-7.18 (m, H), 7.07 (m, H), 3.14 (t, 2H), 2.92 (t, 2H). Example 75 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazoF1,2-alpyridine 75(A) 2-(Chloromethyl)-imidazo[1,2-alpyridine According to the general described in Example 74(A), the conversion of 2 aminopyridine (4.90 g, 52 mmol) afforded 2.66 g of 2-(chloromethyl)-imidazo[l,2 a]pyridine (Yield 40%) as yellow semi-solid. Purification over silicagel chromatography (prepacked 70 g silicagel column, DCM as eluent). LCMS (RT) : 0.81min; MS (ES+) gave m/z: 167.0 Rf (DCM/MeOH: 98/2): 0.50 75(B) 2-(4-(Trimethlsilyl)but-3-ynyl)-imidazo[1.2-alpyridine According to the protocol described in Example 38(C), the conversion of 2 (chloromethyl)-imidazo[1,2-a]pyridine (2.50 g, 15 mmol) afforded 555 mg of 2-(4 (trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 15%) as yellow oil. Purification over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt from 60/40 to 50/50 as eluent). LCMS (RT) : 3.00min; MS (ES+) gave m/z : 243.0 Rf (Cyclohexane/AcOEt: 50/50): 0.30 75(C) 2-(But-3-ynyl)-imidazo[1,2-alpyridine According to the protocol described in Example 38(D), the conversion of 2-(4 (trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (555 mg, 2.29 mmol) afforded 352 mg of 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 90%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 98/2 as eluent). LCMS (RT) : 2.84min; MS (ES+) gave m/z: 171.0 Rf (DCM/MeOH: 98/2) : 0.30 75(D) 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazoF1,2-alpyridine In a dry reaction tube containing in suspension copper iodide (6.5 mg, 0.03 mmol) and triethylamine (2.3 mL), were added 2-bromo-5-fluoropyridine (120 mg, 0.68 mmol) and Pd(PPh 3
)
2 C1 2 (39 mg, 0.03 mmol) under N 2 . A yellow suspension was obtained after 5min of stirring at room temperature. A solution of 2-(but-3-ynyl)-imidazo[l,2 a]pyridine (120 mg, 0.68 mmol) in triethylamine (0.5 mL) was then added under N 2 . Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30min and heated at 80'C overnight. The reaction mixture was concentrated and the crude product was purified by Flash chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 97/3 as eluent) to afford 15 mg of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 8%) as a brown semi-solid. Rf (DCM/MeOH: 95/5) = 0.5. LCMS (RT) : 0.79-2.38min; MS (ES+) gave m/z: 266.0 1 H-NMR (CDC1 3 ), S (ppm) : 8.40 (d, H), 8.08 (d, H), 7.63-7.58 (m, H), 7.42-7.38 (m, 2H), 7.36-7.31 (m, H), 7.17 (t, H), 6.77 (m, H), 3.14 (t, 2H), 2.92 (t, 2H).
WO 2005/123703 PCT/IB2005/002390 133 Example 76 2-(4-(Pyridin-2-ylbut-3-ynylloxazolo[5,4-blpyridine 76(A) 2-(But-3 -yny1)oxazolo[5,4-blpyridine The title compound was prepared in accordance with the general method of Example 8(A), from 3-aminopyridin-2-ol (449 mg, 4.08 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 500 mg (2.90 mmol, 71%) of 2-(but-3-ynyl)oxazolo[5,4-b]pyridine. LCMS (RT) : 3.16min; MS (ES+) gave m/z : 173.0. 76(B) 2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[5,4-blpyridine The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (92 mg, 0.58 mmol) and 2-(but-3-ynyl)oxazolo[5,4 b]pyridine (100 mg, 0.58 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5 to 98:2) to yield 56 mg (0.22 mmol, 39%) of 2-(4-(pyridin-2-yl)but-3-ynyl)oxazolo[5,4-b]pyridine as a colorless oil. LCMS (RT) : 2.91min; MS (ES+) gave m/z : 250.1. Rf (DCM/MeOH 98:2)= 0.2. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.08 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H), 7.17-7.21 (in, 1H), 7.31 (dd, J=5.0 and 8.0, IH), 7.34-7.38 (m, 1H), 7.58-7.62 (in, 1H), 8.00 (dd, J=1.5 and 8.0, 1H), 8.32 (dd, J=1.5 and 4.5, 1H), 8.53-8.54 (d, J=4.5, iH). Example 77 7-Chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzoFdloxazole 77(A) 2-Chloro-4-fluoro-6-nitrophenol 2-Chloro-4-fluorophenol (5.64 g, 38.5 mmol) was added to a solution of acetic acid (16.5 iL), nitric acid (8.66 mL) and water (7.5 mL) at 0 0 C. The reaction mixture was stirred vigorously for 5 hours at 0CC. The resulting precipitate was filtered, washed with water and dried under vacuum to yield 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol, 83%) as a yellow powder. 77(B) 2-Amino-6-chloro-4-fluorophenol The title compound was prepared in accordance with the general method of Example 62(A), from 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 1.66 g (10.3 mmol, 29%) of 2-amino-6-chloro-4-fluorophenol. 77(C) 2-(But-3-ynyl)-7-chloro-5-fluorobenzo[dloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-chloro-4-fluorophenol (1.66 g, 10.3 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 690 mg (3.08 mmol, 30%) of 2-(but-3-ynyl)-7-chloro-5-fluorobenzo[d]oxazole. 77(D) 7-Chloro-5-fluoro-2-(4-(pyridin-2-y1)but-3-yny1)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (141 mg, 0.89 mmol) and 2-(but-3-ynyl)-7-chloro-5 fluorobenzo[d]oxazole (200 mg, 0.89 mmol). The crude residue was purified by flash WO 2005/123703 PCT/IB2005/002390 134 chromatography (DCM/MeOH 99:1) to yield 160 mg (0.53 mmol, 59%) of 7-chloro 5-fluoro-2-(4-(pyridin-2-y1)but-3-ynyl)benzo[d]oxazole as an orange solid. LCMS (RT): 4.38min; MS (ES+) gave m/z: 301.1, 303.0. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.07 (t, J=7.5, 2H), 3.32 (t, J=7.5, 2H), 7.11 (dd, J=2.4 and 9.3, 1H), 7.17-7.24 (m, lH), 7.30 (dd, J=2.4 and 8.1, 1H), 7.37 (d, J=8.1, iH), 7.58-7.66 (m, 1H), 8.54 (d, J=4.8, 1H). Example 78 2-(4-(Pyridin-2-yl)but-3-ynyl)oxazolo[4,5-blpridine 78(A) 2-(But-3-vnyl)oxazolo[4,5-blpyridine The title compound was prepared in accordance with the general method of Example 8(A), from 2-aniinopyridin-3-ol (449 mg, 4.08 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3 to 3:2) to yield 180 mg (1.04 mmol, 26%) of 2-(but-3-ynyl)oxazolo[4,5-b]pyridine as a yellow solid. LCMS (RT) : 3.03min; MS (ES+) gave m/z: 173.0. 78(B) 2-(4-(Pyridin-2-yl)but-3-ynv1)oxazoloF4,5-b1pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (100 mg, 0.49 mmol) and 2-(but-3-yny1)oxazolo[4,5 b]pyridine (100 mg, 0.58 mmol) at room temperature. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 35 mg (0.14 mmol, 29%) of 2-(4-(pyridin-2-yl)but-3-ynyl)oxazolo[4,5-b]pyridine as a brown semi-solid with a purity of 86%. LCMS (RT) : 2.78min; MS (ES+) gave m/z : 250.1. Rf (DCM/MeOH 98:2) = 0.2. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.10 (t, J=7.5, 2H), 3.35 (t, J=7.5, 2H), 7.18-7.21 (m, 1H), 7.26-7.29 (m, IH), 7.34-7.38 (m, 1H), 7.58-7.63 (m, lH), 7.79 (dd, J=1.5 and 8.0, 1H), 8.52-8.56 (m, 1H), 8.54 (dd, J=1.5 and 5.0, 1H). Example 79 2-(4-(Pyridin-2-V1)but-3-ynyl)benzoFdloxazole-5-arbonitrile 79(A) 3-Amino-4-hydroxybenzonitrile . The title compound was prepared in accordance with the general method of Example 62(A), from 4-hydroxy-3-nitrobenzonitrile (1.00 g, 6.09 mmol). 817 mg (6.09 mmol, 100%) of 3-amino-4-hydroxybenzonitrile as an orange solid were obtained and used without purification. 79(B) 2-(But-3-vnvl)benzoldloxazole-5-carbonitrile The title compound was prepared in accordance with the general method of Example 8(A), from 3-amino-4-hydroxybenzonitrile (547 mg, 4.08 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 212 mg (1.08 mmol, 26%) of 2-(buf-3-ynyl)benzo[d]oxazole-5-carbonitrile. LCMS (RT) : 3.79min; MS (ES+) gave m/z: 197.0.
WO 2005/123703 PCT/IB2005/002390 135 79(C) 2-(4-(Pyridin-2-v1)but-3-ynyl)benzo [dloxazole-5-carbonitrile The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (89 mg, 0.43 mmol) and 2-(but-3-ynyl)benzo[d]oxazole-5 carbonitrile (100 mg, 0.51 mmol) at room temperature. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.16 mmol, 37%) of 2 (4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile as a brown solid. LCMS (RT) : 3.53min; MS (ES+) gave m/z : 274.0. Rf (DCM/MeOH 98:2)= 0.2. 'H-NMR (DMSO[D] 6 ), 5 (ppm) : 3.05 (t, J=7.5, 2H), 3.34 (t, J=7.5, 2H), 7.30-7.35 (m, 1H), 7.37-7.41 (m, 1H), 7.72-7.77 (m, 1H), 7.86 (dd, J=1.5 and 8.5, 1H), 7.95 (dd, J=0.5 and 8.5, 1H), 8.34 (d, J=1.5, 1H), 8.49 (d, J=4.5, 1H). Example 80 7-Chloro-5-fluoro-2-(4-(2-methylthiazol-4-1)but-3-yn1)benzoFdloxazole The title compound was prepared in accordance with the general method of Example 1, from 4-iodo-2-methylthiazole (200 mg, 0.89 mmol) and 2-(but-3-ynyl)-7-chloro-5 fluorobenzo[d]oxazole (199 mg, 0.89 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 157 mg (0.49 mmol, 55%) of 7 cbloro-5-fluoro-2-(4-(2-methylthiazol-4-y)but-3-ynyl)benzo[d]oxazole as a yellow solid. LCMS (RT) : 4.78min; MS (ES+) gave m/z : 321.0, 323.0. Rf (cyclohexane/AcOEt 4:1) = 0.2. 'H-NMR (DMSO[D] 6 ), 6 (ppm) : 2.60 (s, 3H), 3.00 (t, J=7.5, 2H), 3.30 (t, J=7.5, 2H), 7.55 (dd, J=2.5 and 8.5, 1H), 7.63 (s, 1H), 7.67 (dd, J=2.5 and 8.5, 1H). Example 81 7-(Trifluoromethvl)-2-4-(pvridin-2-v)but-3-ynvl)benzordloxazole 81(A) 2-Nitro-6-(trifluoromethvl)phenol The title compound was prepared in accordance with the general method of Example 77(A) from 2-(trifluoromethyl)phenol (1.98 g, 12.2 mmol). Reaction time: 5 hours. The resulting precipitate was filtered, washed with water and dried under vacuum to yield 2-nitro-6-(trifluoromethyl)phenol (1.10 g, 5.31 mmol, 43%) as a yellow powder. 81(B) 2-Amino-6-(trifluoromethvl)phenol The title compound was prepared in accordance with the general method of Example 62(A), from 2-nitro-6-(trifluoromethyl)phenol (1.10 g, 5.31 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 510 mg (2.88 mmol, 54%) of 2-amino-6-(trifluoromethyl)phenol. Rf (DCM/MeOH 99:1) = 0.35. 81(C) 2-(But-3-yny1)-7-(trifluoromethl)benzoIdloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-(trifluoromethyl)phenol (510 mg, 2.88 mmol). Reaction time: 3 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 90 mg (0.38 mmol, 13%) of 2-(but-3-ynyl)-7 (trifluoromethyl)benzo[d]oxazole as a red oil.
WO 2005/123703 PCT/IB2005/002390 136 81(D) 7-(Trifluoromethl1-2-(4-(pyridin-2-1)but-3-nvy1)benzofdloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (77 mg, 0.38 nmol) and 2-(but-3-ynyl)-7 (trifluoromethyl)benzo[d]oxazole (90 mg, 0.38 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to DCM/MeOH 99:1) to yield 63 mg (0.20 mmol, 53%) of 7-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3 ynyl)benzo[d]oxazole as a brown solid. LCMS (RT) : 4.33min; MS (ES+) gave m/z : 317.0. Rf (DCM/MeOH 98:2)= 0.2. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.09 (t, J=8.0, 2H), 3.35 (t, J=8.0, 2H), 7.17-7.22 (m, 111), 7.37 (d, J=7.5, 1H), 7.39-7.43 (m, 1H), 7.56 (d, J=8.0, 1H), 7.59-7.63 (in, 1H), 7.88 (d, J=8.0, 1H), 8.50-8.60 (m, 1H). Example 82 7-Bromo-5-fluoro-2-(4-(pyridin-2-l)but-3-nyl)benzofdloxazole 82(A) 2-Bromo-4-fluoro-6-nitrophenol The title compound was prepared in accordance with the general method of Example 77(A) from 2-bromo-4-fluorophenol (1.00 g, 5.24 nimol). Reaction time: 2 hours. The resulting precipitate was filtered, washed with water and dried under vacuum to yield 2-bromo-4-fluoro-6-nitrophenol (1.20 g, 5.08 mmol, 97%) as a yellow powder. 82(B) 2-Amino-6-bromo-4-fluorophenol The title compound was prepared in accordance with the general method of Example 62(A), from 2-bromo-4-fluoro-6-nitrophenol (1.20 g, 5.08 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5 to 98:2) to yield 510 mg (2.48 mmol, 49%) of 2-amino-6-bromo-4-fluorophenol. 82(C) 7-Bromo-2-(but-3 -ynl)-5-fluorobenzordloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-bromo-4-fluorophenol (510 mg, 2.48 mmol). Reaction time: 5 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 223 mg (0.83 mmol, 67%) of 7-bromo-2-(but-3-ynyl)-5 fluorobenzo[d]oxazole. 82(D) 7-Bromo-5-fluoro-2-(4-(pyridin-2-l)but-3-vnT)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (131 mg, 0.83 mmol) and 7-bromo-2-(but-3-ynyl)-5-fluoro benzo[d]oxazole (223 mg, 0.83 mmol). The crude residue was purified by flash chromatography (DCMJMeOH 99:1) to yield 130 mg (0.38 mmol, 45%) of 7-bromo 5-fluoro-2-(4-(pyridin-2-y1)but-3-yny1)benzo[d]oxazole as a brown solid. LCMS (RT) : 4.44min; MS (ES+) gave m/z: 345.0, 346.9. Rf (DCM/MeOH 99:1) = 0.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.08 (t, J=7.9, 2H), 3.33 (t, J=7.9, 2H), 7.19-7.23 (m, 1H), 7.24-7.28 (in, 1H), 7.34 (dd, J=2.3 and 8.0, 1H), 7.36-7.40 (m, 1H), 7.61-7.65 (m, 1H), 8.54-8.57 (in, 1H).
WO 2005/123703 PCT/IB2005/002390 137 Example 83 5-Fluoro-7-phenyl-2-(4-(pyridin-2-yl)but-3-Ynv1)benzo[dloxazole To a solution of 7-bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-yny1)benzo[d]oxazole (100 mg, 0.29 mmol, Example 82) in dioxane/aqueous saturated solution of NaHCO 3 (1:1, 8 mL) were added Pd(PPh 3
)
4 (33 mg, 29 pimol) and phenylboronic acid (53.0 mg, 0.43 mmol). The reaction mixture was stirred at 60'C for 7 hours, then AcOEt and brine were added and the organic phase was discarded. The aqueous phase was extracted tinice with AcOEt. The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 86 mg (0.25 mmol, 87%) of 5-fluoro-7 phenyl-2-(4-(pyridin-2-y)but-3-ynyl)benzo[d]oxazole as an orange oil. LCMS (RT) : 4.83min; MS (ES+) gave m/z : 343.1. Rf (DCM/MeOH 98:2) = 0.2. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.08 (t, J=7.7, 2H), 3.33 (t, J=7.7, 2H), 7.19-7.22 (in, 1H), 7.25-7.29 (in, 1H), 7.32-7.34 (m, 1H), 7.36 (dd, J=2.5 and 8.0, 1H), 7.41-7.46 (2H), 7.47-7.52 (2H), 7.58-7.62 (m, 1H), 7.81-7.84 (in, 1H), 8.54-8.56 (m, 1H). Example 84 2-(4-(2-Chloropyrimidin-4-vl)but-3-vnyl)benzoFdloxazole The title compound was prepared in accordance with the general method of Example 1, from 2,4-dichloropyrimidine (200 mg, 1.34 mmol) and 2-(but-3 ynyl)benzo[d]oxazole (230 mg, 1.34 mmnol, Example 8(A)) at room temperature. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 35 mg (0.12 minmol, 9%) of 2-(4-(2-chloropyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid. LCMS (RT) : 4.1 1min; MS (ES+) gave m/z : 284.0. Example 85 2-Chloro-4-(4-phenvlbut-1-ynyl)pyrimidine The title compound was prepared in accordance with the general method of Example 1, from 2,4-dichloropyrimidine (250 mg, 1.68 mmol) and 1-(but-3-ynyl)benzene (218 mg, 1.68 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 280 mg (1.15 mmol, 69%) of 2-chloro-4-(4 phenylbut-1 -ynyl)pyrimidine as a brown oil. LCMS (RT) : 4.74min; MS (ES+) gave m/z: 243.1. Rf (cyclohexane/AcOEt 9:1) = 0.3. Example 86 4-Bromo-2-(4-(pridin-2-1)but-3-yny)benzofdloxazole 86(A) 3-Methoxy-2-nitrophenylamine Triethylamine (6.29 mL) and diphenyl azidophosphate (6.66 mL, 30.1 mmol) were added to a suspension of 3-methoxy-2-nitrobenzoic acid (3.00 g, 15.2 mmol) in WO 2005/123703 PCT/IB2005/002390 138 toluene (50 mL). The reaction mixture was stirred under reflux for 2 hours, water (10 mL) was added and it was stirred overnight under reflux. After evaporation of the solvent, the residue was dissolved in AcOEt and the resulting solution was filtered through celite. The organic phase was washed with saturated solution of NaHCO 3 , brine, dried over MgS04, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 900 mg (5.35 mmol, 35%) of 3-methoxy-2-nitrophenylamine as a yellow solid. Rf (DCM/MeOH 4:1)= 0.1. 86(B) 1-Bromo-3-methoxy-2-nitrobenzene 3-Methoxy-2-nitro-phenylaniine (360 mg, 2.14 mmol) was dissolved in HBr (48%, 4.8 mL) at 0 0 C. A solution of sodium nitrite (0.16 g, 2.40 mmol) in water (360 p.L) was added dropwise to the stirred solution over one hour period while the temperature was maintained at 0 0 C. Then a cold (0 0 C) freshly prepared solution of CuBr 2 (from CuSO 4 .5H 2 0 (1.0 g) and HBr (48%, 1.0 mL) mixed 30 min. at room temperature to give a dark purple solution) was added at 0 0 C to the reaction mixture. The resulting solution was stirred at 0 0 C for 3 hours and at room temperature for 2 days. The reaction mixture was poured onto ice and neutralized carefully with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The resulting organic phase was washed with brine, dried over MgSO 4 , filtered and evaporated to yield 482 mg (2.08 mmol, 97%) of 1-bromo-3-methoxy-2-nitrobenzene as an orange solid. 86(C) 2-Bromo-6-methoxyphenvlamine The title compound was prepared in accordance with the general method of Example 62(A), from 1-bromo-3-methoxy-2-nitrobenzene (482 mg, 2.08 mmol) to yield 375 mg (1.86 mmol, 89%) of 2-bromo-6-methoxyphenylamine. 86(D) 2-Amino-3-bromophenol BBr 3 (3.71 mL, 3.71 mmol, 1 M in DCM) was added at 0 0 C to a solution of 2-bromo 6-methoxyphenylamine (375 mg, 1.86 mmol) in DCM (10 mL). The reaction mixture was stirred under reflux for 2 hours and was quenched by the addition of MeOH followed by a saturated solution of NaHCO 3 . The aqueous phase was extracted with AcOEt. The resulting organic layer was washed with brine dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3 to DCM) to yield 204 mg (1.08 mmol, 58%) of 2-amino-3 bromophenol as a solid. 86(E) 4-Bromo-2-(but-3-ynvl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3-bromophenol (200 mg, 1.06 mmol). Reaction time: 4 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 100 mg (0.40 mmol, 38%) of 4-bromo-2-(but-3-ynyl)benzo[d]oxazole. 86(F) 4-Bromo-2-(4-(pyridin-2-l)but-3-nyl)benzodloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (63 mg, 0.40 mmol) and 4-bromo-2-(but-3-ynyl) benzo[d]oxazole (100 mg, 0.40 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 60 mg (0.18 mmol, 46%) of 4-bromo-2 (4-(pyridin-2-yl)but-3-yny)benzo[d]oxazole as a brown solid with a purity of 85%.
WO 2005/123703 PCT/IB2005/002390 139 LCMS (RT) : 4.09min; MS (ES+) gave m/z : 327.0, 329.0. Rf (DCM/MeOH 99:1) = 0.1. Example 87 4-Phenyl-2-(4-(pyridin-2-yl)but-3-vnvl)benzordloxazole The title compound was prepared in accordance with the general method of Example 83, from 4-bromo-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole (60 mg, 0.18 mmol, Example 86). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 8 mg (25 prol, 10%) of 4-phenyl-2-(4-(pyridin-2-yl)but-3 ynyl)benzo[d]oxazole as a brown oil with a purity of 80%. LCMS (RT) : 4.89min; MS (ES+) gave m/z : 325.2. Rf (DCM/MeOH 99:1) = 0.1. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.08 (t, J=7.3, 2H), 3.34 (t, J=7.3, 2H), 7.19-7.23 (m, 1H), 7.35-7.42 (3H), 7.47-7.53 (4H), 7.58-7.63 (m, 1H), 7.93-7.98 (2H), 8.53-8.57 (m, 1H). Example 88 4-Chloro-2-(4-(pyridin-2-vl)but-3-ynyl)benzo[dloxazole 88(A) 1-Chloro-3-methoxy-2-nitrobenzene A solution of sodium nitrite (180 mg, 2.60 mmol) in water (0.5 mL) was added dropwise to a solution of 3-methoxy-2-nitro-phenylamine (400 mg, 2.38 mmol, Example 86(A)) in HC1 (37%, 3.9 mL) at 0 0 C over one hour period. Then the reaction mixture was added to a cold (0 0 C) solution of CuC1 2 (640 mg, 4.76 mmol) in HCl (6 N, 3.5 mL). The resulting green solution was stirred at room temperature for 2 days. Then, the reaction mixture was poured onto ice and neutralized carefully with a saturated solution of NaHCO 3 . The aqueous phase was extracted with AcOEt. The resulting organic phase was washed with brine, dried over MgS04, filtered and evaporated to yield 293 mg (1.56 mmol, 66%) of 1-chloro-3-methoxy-2-nitrobenzene as a brown oil. 88(B) 2-Chloro-6-methoxyphenylamine The title compound was prepared in accordance with the general method of Example 62(A), from 1-chloro-3-methoxy-2-nitrobenzene (293 mg, 1.56 mmol) to yield 214 mg (1.36 mmol, 87%) of 2-chloro-6-methoxyphenylamine. Rf (DCM/MeOH 99:1)= 0.3. 88(C) 2-Amino-3-chlorophenol The title compound was prepared in accordance with the general method of Example 86(D), from 2-chloro-6-methoxyphenylamine (397 mg, 2.52 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1 to DCM) to yield 45 mg (0.31 mmol, 12%) of 2-amino-3-chlorophenol as a red oil. 88(D) 2-(But-3-ynyl)-4-chlorobenzordloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3-chlorophenol (50.0 mg, 0.35 mmol). Reaction time: 4 days. The WO 2005/123703 PCT/IB2005/002390 140 crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 20 mg (97 ptmol, 28%) of 2-(but-3-ynyl)-4-chlorobenzo[d]oxazole. 88(E) 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynvl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (15 mg, 97 pmol) and 2-(but-3-ynyl)-4 chlorobenzo[d]oxazole (20 mg, 97 pimol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 3 mg (11 pmol, 11%) of 4-chloro 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid. LCMS (RT) : 3.99min; MS (ES+) gave m/z : 283.0, 285.0. Rf (cyclohexane/AcOEt 4:1) = 0.05. Example 89 5,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzofdloxazole 89(A) 2-(But-3-ynyl)-5,7-difluorobenzofdloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-4,6-difluorophenol (500 mg, 3.45 mmol). Reaction time: 3 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 309 mg (1.49 mmol, 43%) of 2-(but-3-ynyl)-5,7-difluorobenzo[d]oxazole. 89(B) 5,7-Difluoro-2-(4-(pyridin-2-y)but-3-ynyl)benzofdloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (236 mg, 1.49 mmol) and 2-(but-3-ynyl)-5,7-difluoro benzo[d]oxazole (309 mg, 1.49 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 86 mg (0.3 mmol, 20%) of 5,7-difluoro 2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[d]oxazole as a brown solid (M.P. : 93.5-94'C). LCMS (RT) : 4.09min; MS (ES+) gave m/z : 285.1. Rf (DCM/MeOH 99:1) = 0.05. 'H-NMR (CDC1 3 ), S (ppm) : 3.07 (t, J=8.0, 2H), 3.31 (t, J=8.0, 2H), 6.85-6.90 (m, 1H), 7.18-7.22 (2H), 7.35-7.38 (m, 1H), 7.59-7.64 (m, 1H), 8.53-8.56 (m, 1H). Example 90 4-Fluoro-2-(4-(pyridin-2-y)but-3-nyl)benzordloxazole 90(A) 6-Bromo-3-fluoro-2-nitrophenol The title compound was prepared in accordance with the general method of Example 77(A) from 2-bromo-5-fluorophenol (1.16 mL, 10.5 mmol). Reaction time: 6 hours. As there was no preciptate, the reaction mixture was poured onto ice, neutralized with NaOH and extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 6-bromo-3-fluoro-2-nitrophenol (2.30 g, 9.75 mmol, 93%) mixed with 2-bromo-5-fluoro-4-nitrophenol. 90(B) 2-Amino-3-fluorophenol The title compound was prepared in accordance with the general method of Example 62(A), from crude 6-bromo-3-fluoro-2-nitrophenol (2.30 g, 9.75 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5) to yield 56.0 mg (0.44 mmol, 5%) of 2-amino-3-fluorophenol.
WO 2005/123703 PCT/IB2005/002390 141 90(C) 2-(But-3-vnyl)-4-fluorobenzo[d]oxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3-fluorophenol (56 mg, 0.44 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 35 mg (0.18 minol, 42%) of 2-(but-3-ynyl)-4-fluorobenzo[d]oxazole. 90(D) 4-Fluoro-2-(4-(pyridin-2-y)but-3-vnyl)benzordloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (29.2 mg, 0.18 mmol) and 2-(but-3-ynyl)-4 fiuorobenzo[d]oxazole (35 mg, 0.18 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 24 mg (90 ptmol, 49%) of 4 fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid (M.P. = 89 89.5 C). LCMS (RT) : 3.81min; MS (ES+) gave m/z : 267.0. Rf (DCM/MeOH 98:2) = 0.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.06 (t, J=8.0, 2H), 3.29 (t, J=8.0, 2H), 7.04-7.09 (m, 1H), 7.18-7.21 (m, 1H), 7.23 (dd, J=2.5 and 8.0, 111), 7.36 (d, J=8.0, 1H), 7.59-7.63 (2H), 8.52-8.56 (m, 1H). Example 91 7-Methvl-2-(4-(pridin-2-)but-3-nv1)benzo[dloxazole 91(A) 2-Amino-6-methylphenol The title compound was prepared in accordance with the general method of Example 62(A), from 2-methyl-6-nitrophenol (170 mg, 1.11 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 41 mg (0.33 mmol, 30%) of 2-amino-6-methylphenol. Rf (DCM/MeOH 99:1)= 0.1. 91(B) 2-(But-3-ynyl)-7-methylbenzordloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-methylphenol (41 mg, 0.33 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 30 mg (0.16 mmol, 49%) of 2-(but-3-ynyl)-7-methylbenzo[d]oxazole. 91(C) 7-Methv1-2-(4-(pyridin-2-yl)but-3-vnyl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (26 mg, 0.16 mmol) and 2-(but-3-ynyl)-7-methyl benzo[dloxazole (30 mg, 0.16 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 23 mg (87 pmol, 54%) of 7-methyl 2-(4-(pyridin-2-yl)but-3 -ynyl)benzo [d]oxazole as a brown oil. LCMS (RT) : 3.99min; MS (ES+) gave m/z: 263.1. Rf(DCM/MeOH 99:1)= 0.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.51 (s, 3H), 3.07 (t, J=8.0, 2H), 3.30 (t, J=8.0, 2H), 7.11 (d, J=7.5, 1H), 7.17-7.24 (2H), 7.36 (d, J=7.5, 1H), 7.51 (d, J=8.0, 1H), 7.59-7.63 (m, 1H), 8.54 (d, J=4.0, 1H).
WO 2005/123703 PCT/IB2005/002390 142 Example 92 2-(4-(Pyridin-2-yl)but-3-yny1)benzordloxazole-7-carbonitrile 92(A) 2-(But-3-ynyl)benzofdloxazole-7-carbonitrile The title compound was prepared in accordance with the general method of Example 8(A), from 3-amino-2-hydroxybenzonitrile (500 mg, 3.73 mmol). Reaction time: 3 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 535 mg (2.73 mmol, 73%) of 2-(but-3-ynyl)benzo[d]oxazole-7 carbonitrile. 92(B) 2-(4-(Pyridin-2-yLbut-3-vylbenzo[dloxazole-7-carbonitrile The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (161 mg, 1.02 mmol) and 2-(but-3-ynyl)benzo[d]oxazole-7 carbonitrile (200 mg, 1.02 mmol). The crude residue was purified by flash chromatography (DCMIMeOH 99:1) to yield 48 mg (0.18 mmol, 17%) of 2-(4 (pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-7-carbonitrile as a yellow solid (M.P. = 126-126.5-C). LCMS (RT) : 3.61min; MS (ES+) gave m/z: 274.1. 1H-NMR (CDC1 3 ), 5 (ppm) : 3.10 (t, J=7.5, 2H), 3.36 (t, J=7.5, 2H), 7.18-7.22 (m, 1H), 7.39 (d, J=7.5, 1H), 7.39-7.44 (in, 1H), 7.59-7.64 (2H), 7.93 (dd, J=1.0 and 8.0, 1H), 8.54 (d, J=4.5, 1H). Example 93 7-Chloro-4-fluoro-2-(4-(pyridin-2-vl)but-3-vnvl)benzo[d1oxazole 93(A) 6-Chloro-3-fluoro-2-nitrophenol The title compound was prepared in accordance with the general method of Example 77(A) from 2-chloro-5-fluoro-phenol (2.00 g, 13.6 mmol). Reaction time: 5 hours. The reaction mixture was poured onto ice and extracted with AcOEt. The organic phase was washed with saturated solution of NaHCO 3 , water, dried over MgSO 4 , filtered and evaporated to yield 6-chloro-3-fluoro-2-nitrophenol (2.56 g, 13.4 mmol). 93(B) 2-Amino-6-chloro-3-fluorophenol The title compound was prepared in accordance with the general method of Example 62(A), from 6-chloro-3-fluoro-2-nitrophenol (2.56 g, 13.4 mmol). Reaction time: I day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 1.01 g (6.26 mmol, 47%) of 2-amino-6-chloro-3-fluorophenol. 93(C) 2-(But-3-ynyl)-7-chloro-4-fluoro-benzo[dloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-chloro-3-fluorophenol (1.01 g, 6.26 mmol). Reaction time: 3 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 176 ing (0.79 inmol, 13%) of 2-(but-3-ynyl)-7-chloro-4-fluoro benzo[d]oxazole. 93(D) 7-Chloro-4-fluoro-2-(4-(pyridin-2-l)but-3-nl)benzordloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (124 mg, 0.79 mnol) and 2-(but-3-ynyl)-7-chloro-4-fluoro- WO 2005/123703 PCT/IB2005/002390 143 benzo[d]oxazole (176 mg, 0.79 rmmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 30 mg (99 pLmol, 13%) of 7-cbloro-4 fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid (M.P. = 102 103-C). LCMS (RT): 4.31min; MS (ES+) gave m/z: 301.0, 303.0. 'H-NMR (CDCl 3 ), 5 (ppm) : 3.09 (t, J=8.0, 2H), 3.34 (t, J=8.0, 2H), 6.99-7.04 (m, 1H), 7.18-7.22 (m, 1H), 7.24-7.29 (m, 1H), 7.36-7.40 (m, 1H), 7.60-7.64 (m, 1H), 8.53-8.55 (m, 1H). Example 94 7-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 94(A) 3-Aminobenzene-1,2-diol The title compound was prepared in accordance with the general method of Example 62(A), from 3-nitrobenzene-1,2-diol (1.00 g, 6.45 mmol). 392 mg (3.13 mmol, 49%) of 3-aminobenzene-1,2-diol as a brown solid were obtained and used without purification. 94(B) 2-(But-3-ynv1)benzoFdloxazol-7-ol The title compound was prepared in accordance with the general method of Example 8(A), from 3-aminobenzene-1,2-diol (392 mg, 3.13 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to 7:3) to yield 130 mg (0.69 mmol, 22%) of 2-(but-3-ynyl)benzo[d]oxazol-7-ol. 94(C) 2-(4-(Pyridin-2-y)but-3-ynyl)benzo[dloxazol-7-ol The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (110 mg, 0.69 mol) and 2-(but-3-ynyl)benzo[d]oxazol-7-ol (130 mg, 0.69 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 10 mg (38 pmol, 5%) of 2-(4-(pyridin-2-yl)but-3 ynyl)benzo[d]oxazol-7-ol. Rf (DCM/MeOH 98:2)= 0.1. 94(D) 7-Methoxv-2-(4-(pyridin-2-yl)but-3-yny1)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 72, from 2-(4-pyridin-2-yl-but-3-ynyl)-benzo[djoxazol-7-ol (10 mg, 38 pImol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 3.7 mg (13 jamol, 35%) of 7-methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil with a purity of 82%. LCMS (RT) : 3.56min; MS (ES+) gave m/z : 279.2. Rf(DCM/MeOH 99:1)= 0.1. IH-NMR (CDC1 3 ), 5 (ppm) : 3.08 (t, J=8.1, 2H), 3.31 (t, J=8.1, 2H), 4.03 (s, 3H), 6.86 (d, J=8.1, 1H), 7.18-7.22 (m, 1H), 7.22-7.26 (m, 1H), 7.32 (dd, J=0.8 and 8.0, 1H), 7.39 (d, J=8.0, 1H), 7.59-7.64 (m, 1H), 8.53-8.57 (m, 1H). Example 95 7-Isopropyl-2-(4-(pyridin-2-vl)but-3-ynyllbenzo~dloxazole WO 2005/123703 PCT/IB2005/002390 144 95(A) 2-Isopropyl-6-nitrophenol The title compound was prepared in accordance with the general method of Example 77(A) from 2-isopropylphenol (2.00 g, 14.7 mmol). Reaction time: 6 hours. The reaction mixture was poured onto ice and extracted with AcOEt. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 2 isopropyl-6-nitrophenol (2.50 g, 13.8 mmol, 94%). 95(B) 2-Amino-6-isopropvlphenol The title compound was prepared in accordance with the general method of Example 62(A), from 2-isopropyl-6-nitrophenol (2.50 g, 13.8 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 974 mg (6.44 mmol, 47%) of 2-amino-6-isopropylphenol. 95(C) 2-But-3-ynyl-7-isopropyl-benzo[dloxazole The title compound was prepared in accordance with.the general method of Example 8(A), from 2-amino-6-isopropylphenol (974 mg, 6.44 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 55 mg (0.26 mmol, 4%) of 2-(but-3-ynyl)-7-isopropyl-benzo[d]oxazole. 95(D) 7-Isopropyl-2-(4-(pyridin-2-vl)but-3-vnv1)benzordloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (41 mg, 0.26 mmol) and 2-(but-3-ynyl)-7-isopropyl benzo[d]oxazole (55 mg, 0.26 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 4.2 mg (14 pmol, 6%) of 7-isopropyl-2 (4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a red oil. LCMS (RT) : 4.56min; MS (ES+) gave m/z : 291.2. Rf (DCM/MeOH 97.5:2.5) = 0.3. 'H-NMR (CDCl 3 ), 8 (ppm) : 1.37 (d, J=7.0, 6H), 3.07 (t, J=8.0, 2H), 3.31 (t, J=8.0, 2H), 3.31-3.37 (m, 1H), 7.15 (dd, J=1.0 and 7.5, 1H), 7.17-7.21 (m, 1H), 7.22-7.26 (m, 1H), 7.34-7.37 (m, 1H), 7.52 (dd, J=1.0 and 8.0, 1H), 7.58-7.62 (m, 1H), 8.53 8.56 (m, 1H). Example 96 4,7-Difluoro-2-(4-(pyridin-2-y1)but-3-ynyl)benzordloxazole 96(A) 3,6-Difluoro-2-nitrophenol The title compound was prepared in accordance with the general method of Example 77(A) from 2,5-difluorophenol (1.00 g, 7.69 mmol). Reaction time: 6 hours. The reaction mixture was poured onto ice and extracted with AcOEt. The organic phase was washed with brine, dried over MgS04, filtered and evaporated to yield 3,6 difluoro-2-nitrophenol (1.28 g, 7.30 mmol). 96(B) 2-Amino-3,6-difluorophenol The title compound was prepared in accordance with the general method of Example 62(A), from 3,6-difluoro-2-nitrophenol (1.28 g, 7.30 mmol). Reaction time: 4 days. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 836 mg (5.76 mmol, 79%) of 2-amino-3,6-difluorophenol.
WO 2005/123703 PCT/IB2005/002390 145 96(C) 2-(But-3-ynyl)-4,7-difluoro-benzordloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3,6-difluorophenol (836 mg, 5.76 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 90 mg (0.43 mmol, 7%) of 2-(but-3-ynyl)-4,7-difluoro-benzo[d]oxazole. 96(D) 4,7-Difluoro-2-(4-(pyidin-2-l)but-3-ynv)benzordloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (69 mg, 0.43 mmol) and 2-(but-3-ynyl)-4,7-difluoro benzo[d]oxazole (90 mg, 0.43 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 17 mg (61 mol, 14%) of 4,7 difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid. LCMS (RT) : 3.99min; MS (ES+) gave m/z : 285.1. Rf (DCM/MeOH 98.5:1.5) = 0.1. 'H-NMR (CDCls), 5 (ppm) : 3.09 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H), 6.94-7.05 (2H), 7.18-7.22 (m, 1H), 7.36-7.39 (m, 1H), 7.59-7.64 (m, 1H), 8.53-8.56 (m, 1H). Example 97 7-Fluoro-4-(trifluoromethyl)-2-(4-(pridin-2-1)but-3-nl)benzordloxazole 97(A) 6-Fluoro-2-nitro-3-(trifluoromethvl)phenol The title compound was prepared in accordance with the general method of Example 77(A) from 2-fluoro-5-(trifluoromethyl)phenol (1.00 g, 5.55 mmol). Reaction time: 6 hours. The reaction mixture. was poured onto ice and extracted with AcOEt. The organic phase was washed with brine, dried over MgS04, filtered and evaporated to yield 6-fluoro-2-nitro-3-(trifluoromethyl)phenol (1.21 g, 5.39 mnmol). 97(B) 2-Anino-6-fluoro-3-(trifluoromethvl)phenol The title compound was prepared in accordance with the general method of Example 62(A), from 6-fluoro-2-nitro-3-(trifluoromethyl)phenol (1.21 g, 5.38 mmol). Reaction time: I day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 320 mg (1.64 mmol, 30%) of 2-amino-6-fluoro-3 (trifluoromethyl)phenol. 97(C) 2-(But-3- vnvl)-7-fluoro-4-(trifluoromethyl)-benzo[dloxazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-fluoro-3-(trifluoromethyl)phenol (320 mg, 1.64 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 80 mg (0.31 mmol, 19%) of 2-(but-3-ynyl)-7 fluoro-4-(trifluoromethyl)-benzo[d]oxazole. 97(D) 7-Fluoro-4-(trifluoromethvl)-2-(4-(pyridin-2-vl)but- 3 -vny1)benzodloxazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (49 mg, 0.31 mmol) and 2-(but-3-ynyl)-7-fluoro-4 (trifluoromethyl)-benzo[d]oxazole (80 mg, 0.31 mmol). The crude residue was purified by flash chromatography (DCM/4eOH 98.5:1.5) to yield 15 mg (44 pmol, 14%) of 7-fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-y1)but-3-ynyl)benzo[d]oxazole as an orange solid. LCMS (RT) : 4.44min; MS (ES+) gave m/z : 335.1.
WO 2005/123703 PCT/IB2005/002390 146 Rf (DCM/MeOH 98.5:1.5) = 0.2. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.09 (t, J=8.0, 2H), 3.39 (t, J=8.0, 211), 7.13-7.18 (m, 1H), 7.19-7.22 (m, 1H), 7.35-7.38 (m, 1H), 7.55-7.59 (m, 1H), 7.60-7.64 (m, 1H), 8.52-8.56 (m, 1H). Example 98 2-(4-(Pyrimidin-4-yl)but-3-ynyl)benzo[dloxazole 98(A) 4-Chloropyrimidine Pyrimidin-4-ol (200 mg, 2.08 mmol) was dissolved in phosphorous chloride (2 mL), the reaction mixtue was stirred for 1 hour at 100 C and poured onto ice. The aqueous phase was neutralized with NaOH and extracted with AcOEt. The organic phase was washed with brine, dried over MgSO 4 , filtered and evaporated to yield 4 chloropyrimidine (85 mg, 0.74 nnnol, 36%) as an orange oil. 98(B) 2-(4-(Pyrimidin-4-vl)but-3 -vnvl)benzo[dloxazole The title compound was prepared in accordance with the general method of Example 1, from 4-chloropyrimidine (85 mg, 0.74 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (127 mg, 0.74 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 32 mg (128 Imol, 17%) of 2-(4-(pyrimidin-4 yl)but-3-ynyl)benzo[d]oxazole as a white solid. Rf (cyclohexane/AcOEt 1:1) = 0.2. 'H-NMR (CDCl 3 ), S (ppm) : 3.12 (t, J=7.9, 2H), 3.32 (t, J=7.9, 2H), 7.31 (dd, J=1.1 and 5.1, 1H), 7.33-7.36 (2H), 7.50-7.54 (m, 1H), 7.69-7.72 (m, 1H), 8.67 (d, J=5.1 1H), 9.15 (d, J=1.1, 1H). Example 99 N-(3-Chlorophenvl)-N-methyl-5-(pidin-2-yllpent-4-vnamide 99(A) Pent-4-ynoic acid (3-chloro-phenv1)-methyl-amide Oxayl chloride (89 ptL, 1.02 mmol) was added to a solution of pent-4-ynoic acid (50 mg, 0.51 mmol) in DCM (3 mL). The reaction mixture was stirred at 50'C for 1 hour, was cooled to 0 0 C and was added dropwise to a solution of (3-chloro-phenyl)-methyl amine (62 ptL, 0.51 mmol). The reaction mixture was stirred for 2 hours at room temperature. After evaporation of the solvent, the crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 100 mg (0.45 mmol, 88%) of pent-4 ynoic acid (3-chloro-phenyl)-methyl-amide. LCMS (RT) : 3.94min; MS (ES+) gave m/z : 222.0. 99(B) N-(3-Chlorophenvl)-N-methyl-5-(pyridin-2-vllpent-4-vnamide The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (80 mg, 0.51 mmol) and pent-4-ynoic acid (3-chloro phenyl)-methyl-amide (113 mg, 0.51 nmol). The crude residue was purified by C 18 flash chromatography to yield 51 mg (0.17 mmol, 33%) of N-(3-chlorophenyl)-N methyl-5-(pyridin-2-yl)pent-4-ynamide as a brown liquid. LCMS (RT) : 3.73min; MS (ES+) gave m/z : 299.1, 301.1.
WO 2005/123703 PCT/IB2005/002390 147 'H-NMR (CDC1 3 ), a (ppm) : 2.39-2.50 (m, 2H), 2.76 (t, J=7.5, 2H), 3.28 (s, 3H), 7.11-7.15 (m, 1H), 7.16-7.20 (m, 1H), 7.24-7.27 (in, 1H), 7.32-7.39 (in, 1H), 7.45 7.50 (m, 1H), 7.58-7.63 (m, 1H), 7.65-7.71 (m, 1H), 8.52 (d, J=4.8, 1H). Example 100 7-Chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynl)benzo[dlthiazole 100(A) 2-Amino-6-chloro-3-methyl-benzenethiol To a solution of NaOH (1 ON, 8.0 mL) was added 7-chloro-4-methyl-benzothiazol-2 ylamine (530 mg, 2.67 mmol) and ethylene glycol (10 mL) then the reaction mixture was stirred at 150'C for 1 day. After being cooled down, the reaction mixture was filtered. The filtrate was extracted with DCM. The aqueous phase was acidified with HC1 IN and extracted with DCM. Then, the combined organic phases were washed with brine, dried over MgSO 4 , filtered and evaporated to yield 2-amino-6-chloro-3 methyl-benzenethiol (252 mg, 1.45 mmol, 54%) as a yellow oil. 100(B) 2-But-3-ynyl-7-chloro-4-methyl-benzordlthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-chloro-3-methyl-benzenethiol (252 mg, 1.45 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 30 mg (0.13 mmol, 9%) of 2-but-3-ynyl-7-chloro 4-methyl-benzo[d]thiazole as an orange oil. 100(C) 7-Chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-nyllbenzordlthiazo1e The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (20 mg, 0.13 mmol) and 2-but-3-ynyl-7-chloro-4-methyl benzo[d]thiazole (30 mg, 0.13 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 2.9 mg (9.3 pmol, 7%) of 7 chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil. LCMS (RT) : 5.04min; MS (ES+) gave m/z: 313.1, 315.0. Rf (DCM/MeOH 97:3) = 0.3. 'H-NMR (CDC1 3 ), a (ppm) : 2.70 (s, 3H), 3.05 (t, J=7.5, 2H), 3.46 (t, J=7.5, 2H), 7.18-7.22 (2H), 7.24-7.27 (m, 1H), 7.37-7.40 (m, 1H), 7.60-7.64 (m, 1H), 8.54-8.57 (m, 1H). Example 101 4-Fluoro-2-(4-(pyridin-2-y)but-3-ynyl)benzordlthiazole 101(A) 2-Amino-3-fluoro-benzenethiol The title compound was prepared in accordance with the general method of Example 100(A), from 4-fluoro-benzothiazol-2-ylamine (603 mg, 3.58 mmol) to yield 2 amino-3-fluoro-benzenethiol (513 mg, 3.58 mmol) as a yellow solid. 101(B) 2-But-3-ynyl-4-fluoro-benzo dlthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3-fluoro-benzenethiol (513 mg, 3.58 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt WO 2005/123703 PCT/IB2005/002390 148 9:1) to yield 378 mg (1.84 mmol, 51%) of 2-but-3-ynyl-4-fluoro-benzo[d]thiazole as an orange oil. 101(C) 4-Fluoro-2-(4-(pyridin-2-vl)but-3-vnyl)benzo[dlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (291 mg, 1.84 mmol) and 2-but-3-ynyl-4-fluoro benzo[d]thiazole (378 mg, 1.84 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 10 mg (37 ptmol, 2%) of 4-fluoro-2-(4 (pyridin-2-yl)but-3-yny)benzo[d]thiazole as a yellow solid. LCMS (RT) : 3.89min; MS (ES+) gave m/z : 283.0. Rf (DCM/MeOH 98:2) = 0.1. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.05 (t, J=7.5, 2H), 3.48 (t, J=7.5, 2H), 7.15-7.22 (2H), 7.30-7.35 (m, 1H), 7.38 (d, J=8.0, 1H), 7.60-7.65 (2H), 8.55 (d, J=5.0, 1H). Example 102 4,7-Dimethyl-2-(4-(pyridin-2-vl)but-3-ynv1)benzofdlthiazole 102(A) 2-Amino-3,6-dimethyl-benzenethiol The title compound was prepared in accordance with the general method of Example 100(A), from 4,7-dimethyl-benzothiazol-2-ylamine (580 mg, 3.25 mmol) to yield 2 amino-3,6-dimethyl-benzenethiol (200 mg, 1.30 mmol, 40%) as a yellow oil. 102(B) 2-But-3-ynyl-4,7-dimethyl-benzofdlthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3,6-dimethyl-benzenethiol (200 mg, 1.30 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 63 mg (0.29 mmol, 22%) of 2-but-3-ynyl-4,7-dimethyl-benzo[d]thiazole. 102(C) 4,7-Dimethyl-2-(4-(pyridin-2-vl)but-3-yny1)benzord]thiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (46 mg, 0.29 mmol) and 2-but-3-ynyl-4,7-dimethyl benzo[d]thiazole (63 mg, 0.29 mmol). The crude residue was purified by flash chromatography (DCM/IMeOH 99:1 to 98:2) to yield 15 mg (52 ptmol, 18%) of 4,7 dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid. LCMS (RT) : 4.73min; MS (ES+) gave m/z : 293.1. Rf (DCM/MeOH 98:2) = 0.1. 'H-NMR (CDC1 3 ), S (ppm) : 2.50 (s, 3H), 2.70 (s, 3H), 3.04 (t, J=7.5, 2H), 3.47 (t, J=7.5, 2H), 7.06 (d, J=7.5, 1H), 7.18 (d, J=7.5, 1H), 7.19-7.21 (m, 1H), 7.36-7.39 (m, 1H), 7.60-7.64 (m, 1H), 8.54-8.57 (m, 1H). Example 103 4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzofdlthiazole 103(A) 2-Anino-3-methyl-benzenethiol The title compound was prepared in accordance with the general method of Example 100(A), from 4-methyl-benzothiazol-2-ylanine (1.00 g, 6.09 mmol) to yield 2-amino 3-methyl-benzenethiol (463 mg, 3.33 mnol, 55%).
WO 2005/123703 PCT/IB2005/002390 149 103(B) 2-But-3-ynyl-4-methyl-benzofdlthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3-methyl-benzenethiol (463 mg, 3.33 mnmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 246 mg (1.22 mmol, 37%) of 2-but-3-ynyl-4-metyl-benzo[d]thiazole. 103(C) 4-Methyl-2-(4-(pyridin-2-l)but-3-nYlIbenzoFdlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (193 mg, 1.22 mmol) and 2-but-3-ynyl-4-methyl benzo[d]thiazole (246 mg, 1.22 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 86 mg (0.31 mmol, 25%) of 4 methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil. LCMS (RT) : 4.33min; MS (ES+) gave m/z : 279.1. Rf (DCM/MeOH 98:2)= 0.2. 1 H-NMR (CDC1 3 ), S (ppm) : 2.74 (s, 3H), 3.04 (t, J=7.5, 2H), 3.46 (t, J=7.5, 2H), 7.18-7.22 (m, 1H), 7.24-7.26 (2H), 7.36-7.39 (in, 1H), 7.59-7.64 (in, 1H), 7.65-7.70 (in, 1H), 8.54-8.57 (in, 1H). Example 104 5-Fluoro-2-(4-(pyridin-2-vl)but-3-ynyl)benzordlthiazole 104(A) 2-Ainino-4-fluoro-benzenethiol The title compound was prepared in accordance with the general method of Example 100(A), from 5-fluoro-benzothiazol-2-ylamine (520 mg, 3.09 mmol) to yield 2 amino-4-fluoro-benzenethiol (443 mg, 3.09 mmol) as a yellow solid. 104(B) 2-But-3-ynvl-5-fluoro-benzordlthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-4-fluoro-benzenethiol (443 mg, 3.09 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 286 mg (1.39 mmol, 45%) of 2-but-3-ynyl-5-fluoro-benzo[d]thiazole. 104(C) 5-Fluoro-2-(4-(pyridin-2-vl)but-3-vnv1)benzo[dthiaole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (220 mg, 1.39 mmol) and 2-but-3-ynyl-5-fluoro benzo[d]thiazole (286 mg, 1.39 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 38 mg (0.13 mmol, 10%) of 5 fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as an orange solid. LCMS (RT) : 3.98min; MS (ES+) gave m/z: 283.1. Rf (DCM/MeOH 98:2) = 0.2. 'H-NMR (CDC1 3 ), S (ppm) : 3.03 (t, J=7.5, 2H), 3.43 (t, J=7.5, 2H), 7.17-7.22 (2H), 7.36-7.38 (in, 1H), 7.53 (dd, J=2.5 and 8.5, 1H), 7.59-7.64 (m, IH), 7.92 (dd, J=4.5 and 8.5, 1H), 8.54-8.56 (m, 1H). Example 105 4-Chloro-2-(4-(pyridin-2-1)but-3-nv1)benzordlthiazole WO 2005/123703 PCT/IB2005/002390 150 105(A) 2-Amino-3-chloro-benzenethiol The title compound was prepared in accordance with the general method of Example 100(A), from 4-chloro-benzothiazol-2-ylamine (584 mg, 3.16 mmol) to yield 2 amino-3-chloro-benzenethiol (364 mg, 2.28 mmol, 74%) as a yellow solid. 105(B) 2-But-3-ynv1-4-chloro-benzo[dthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-3-chloro-benzenethiol (364 mg, 2.28 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 233 mg (1.05 mmol, 46%) of 2-but-3-ynyl-4-chloro-benzo[dthiazole. 105(C) 4-Chloro-2-(4-(pyridin-2-vl)but-3-vnyl)benzofdlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (166 mg, 1.05 mmol) and 2-but-3-ynyl-4-chloro benzo[d]thiazole (233 mg, 1.05 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 46 mg (0.15 mmol, 14%) of 4 chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil. LCMS (RT) : 4.18min; MS (ES+) gave m/z : 299.1, 301.1. Rf (DCM/MeOH 98:2)= 0.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.04 (t, J=7.5, 2H), 3.50 (t, J=7.5, 2H), 7.18-7.22 (m, 1H), 7.27-7.32 (m, 1H), 7.39 (d, J=7.5, 1H), 7.49 (dd, J=1.0 and 8.0, 1H), 7.60-7.65 (m, 1H), 7.75 (dd, J=1.0 and 8.0, 1 H), 8.53-8.59 (m, 1H). Example 106 N-(2-Chlorophenvl)-N-methyl-5-(pyrdin-2-yl)pent- 4 -ynamide 106(A) Pent-4-vnoic acid (2-chloro-pheny)-methyl-amide The title compound was prepared in accordance with the general method of Example 99(A), from (2-chloro-phenyl)-methyl-amine (0.19 mL, 1.53 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 220 mg (1.00 mmol, 65%) of pent-4-ynoic acid (2-chloro-phenyl)-methyl-amide. LCMS (RT) : 3.91min; MS (ES+) gave m/z: 222.0. 106(B) N-(2-Chlorophenv-N-methyl-5-(yrdin-2-v1)pent-4-vnmide The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (157 mg, 1.00 mmol) and pent-4-ynoic acid (2-chloro phenyl)-methyl-amide (220 mg, 1.00 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (66 tmol, 7%) of N-(2 chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brown liquid. LCMS (RT) : 3.61min; MS (ES+) gave m/z : 299.1. 'H-NMR (CDC1 3 ), 8 (ppm) : 2.26-2.40 (m, 2H), 2.68-2.81 (m, 211), 3.22 (s, 3H), 7.14 7.19 (m, 1H), 7.28-7.40 (411), 7.49-7.53 (m, 1H), 7.55-7.61 (m, 1H), 8.49 (d, J=6.0, 1H). Example 107 1-Methyl-2-(4-(pyridin-2-v3but-3-ynv 1)-H-benzoFdlimidazole WO 2005/123703 PCT/IB2005/002390 151 107(A) 2-Chloromethyl-1-methvl-1H-benzoimidazole A solution of (1-imethyl-1H-benzoimidazol-2-yl)-methanol (500 mg, 3.08 mmol) and SOCl 2 (1.1 mL) in DCM (2 mL) was stirred at room temperature for 3 hours. After evaporation of the solvents, 2-chloromethyl-1-methyl-lH-benzoimidazole (556 mg, 3.08 mmol) was obtained and was used without any purification. 107(B) 1-Methyl-2-(4-trimethylsilanvl-but-3-vnyl)-1H-benzoimidazole n-BuLi (1.35 mL, 3.39 mmol, 2.5 M) was added to a solution of trimethyl-prop-l ynyl-silane (0.55 mL, 3.69 mmol) in THF (1 mL) at -78'C. After 2 hours, a solution of 2-clioromethyl-1-methyl-1H-benzoimidazole (556 mg, 3.08 mmol) in THF (8 mL) was added to the reaction tnixture at -78'C then the reaction mixture was stirred for 30 min. at -78 0 C and 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgSO 4 , filtered and evaporated to yield 1-methyl-2-(4-trimethylsilanyl but-3-ynyl)-1H-benzoimidazole (178 mg, 0.69 mmol, 23%). LCMS (RT) : 3.13min; MS (ES+) gave m/z : 257.2. 107(C) 2-But-3-ynvl-1-methyl-1H-benzoimidazole TBAF (0.24 mL, 0.83 mmol) was added to a solution of 1-methyl-2-(4 trimethylsilanyl-but-3-ynyl)-lH-benzoimidazole (178 mg, 0.69 mmol) in THF (2.5 mL) and the reaction mixture was stirred for 2 hours at room temperature. After the addition of water, the solvent was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with brine, dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 90 mg (0.49 mmol, 70%) of 2-but-3 -ynyl- 1-methyl 1 H-benzoinidazole as a brown solid. LCMS (RT): 1.99min; MS (ES+) gave m/z: 185.2. 107(D) 1-Methyl-2-(4-(pyridin-2-vl)but-3-vnvl)-1H-benzo[dlimidazole The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (100 mg, 0.49 mmol) and 2-but-3-ynyl-l-methyl-1H benzoimidazole (90 mg, 0.49 mmol). Reaction time: 18 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 39 mg (0.15 mmol, 31%) of 1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a brown solid. LCMS (RT) : 2.33min; MS (ES+) gave m/z : 262.1. 'H-NMR (CDCl 3 ), S (ppm) : 3.10 (t, J=7.2, 2H), 3.27 (t, J=7.2, 2H), 3.81 (s, 3H), 7.19-7.23 (m, 1H), 7.24-7.30 (2H), 7.31-7.34 (m, 1H), 7.36 (d, J=7.8, 1H), 7.59-7.65 (m, 1H), 7.72-7.76 (m, 1H), 8.56 (d, J=4.3, 1H). Example 108 2-(4-(Pyridin-2-vl)but-3-vnvl)-2H-indazole 108(A) 2-(4-Trimethylsilanvl-but-3-ynvl)-2H-indazole and 1-(4-trimethylsilanyl-but 3-ynyl)-1H-indazole A suspension of (4-bromo-but-1-ynyl)-trimethyl-silane (374 mg, 1.83 -mimol), indazole (200 mg, 1.69 mol) and K 2 C0 3 (459 mg, 3.32 mmol) in acetone (2 mL) was heated at 150'C for 900 s in a microwave. After the addition of water, acetone was evaporated. The aqueous phase was extracted with DCM. The organic phase was WO 2005/123703 PCT/IB2005/002390 152 washed with brine, dried over MgSO 4 , filtered and evaporated to yield 250 ng (1.03 mmol, 62%) of 2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole - and 1-(4 trimethylsilanyl-but-3-ynyl)-1H-indazole. 108(B) 2-(But-3-ynyl)-2H-indazole and 1-(but-3-ynyl)-1H-indazole TBAF (1.24 mL, 1.24 mmol) was added to a solution of 2-(4-trimethylsilanyl-but-3 ynyl)-2H-indazole and 1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole (250 mg, 1.03 mmol) in THF (5 mL) and the reaction mixture was stirred for 2 hours at room temperature. After the addition of water, the solvent was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with brine, dried over MgSO 4 , filtered and evaporated. The crude residue was purified by bulb-to-bulb distillation (0.2 mbar, 100-1201C) to yield 160 mg (0.94 nmol, 91%) of 2-(but-3 ynyl)-2H-indazole and 1-(but-3-ynyl)-1H-indazole. 108(C) 2-(4-(Pyridin-2-yl)but-3-vny1)-2H-indazole and 1-(4-(pyridin-2-y)but-3 vny1)-1H-indazole A solution of 2-(but-3-ynyl)-2H-indazole and 1-(but-3-ynyl)-lH-indazole (160 mg, 0.94 mmol) in DMF (0.5 mL) was added to a suspension of Cul (8.9 mg, 47 ptmol), Et 3 N (2.5 mL), Pd(PPh 3
)
2
C
2 (33 mg, 47 pmol), PPh 3 (6.2 mg, 23 tmol) and 2 bromopyridine (149 mg, 0.94 mmol). The reaction mixture was heated at 120'C for 900 s in a microwave. The reaction mixture was quenched with water, Et 3 N was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with a saturated solution of NH 4 0H, brine, dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH 4 0H 95:4:1 to 94:4:2) to yield 6.8 mg (27 pimol, 3%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a yellow solid and 4.6 mg (19 pimol, 2%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H indazole as an orange oil. 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-indazole: LCMS (RT): 3.53min; MS (ES+) gave m/z : 248.2. Rf (DCM/MeOH 98:2) = 0.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.18 (t, J=6.9, 2H), 4.69 (t, J=6.9, 2H), 7.06-7.11 (m, 1H), 7.20-7.25 (m, 1H), 7.28-7.33 (2H), 7.59-7.64 (m, 1H), 7.65-7.68 (m, 1H), 7.72 (dd, J=0.9 and 8.8, 1 H), 8.08 (d, J=0.9, 1H), 8.57 (d, J=4.3, 1H). 1-(4-(Pyridin-2-yl)but-3-vnyl)-iH-indazole: LCMS (RT) : 3.24min; MS (ES+) gave m/z : 248.2. Rf(DCM/MeOH 98:2) = 0.03. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.07 (t, J=7.3, 2H), 4.68 (t, J=7.3, 2H), 7.14-7.23 (3H), 7.36-7.42 (m, 1H), 7.51-7.55 (in, 1H), 7.57-7.62 (m, 1H), 7.75 (d, J=8.1, 1H), 8.04 (s, 1 1H), 8.52-8.57 (m, 1H). Example 109 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[dl[1,2,3]triazole Method A 109(A) 2-(4-Trimethylsilanyl-but-3-ynyl)-2H-benzo[dlF1,2,31triazole and 1-(4 trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3 triazole The title compounds were prepared in accordance with the general method of Example 108(A), from benzotriazole (116 mg, 0.97 mmol) to yield 157 mg (0.64 WO 2005/123703 PCT/IB2005/002390 153 mmol, 67%) of 2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(4 trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3]triazole. 109(B) 2-(But-3-ynvl)-2H-benzofdl[1,2,31triazole and 1-(but-3-ynyl)-1H benzoFdl[1,2,31triazole The title compounds were prepared in accordance with the general method of Example 108(B), from 2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole and 1-(4-trimethylsilanyl-but-3-ynyl)-1H-benzo[d][1,2,3]triazole (157 mg, 0.64 mmol) to yield after bulb-to-bulb distillation (0.2 mbar, 80-100'C), 90 mg (0.53 mmol, 83%) of 2-(but-3-yny)-2H-benzo[d][1,2,3]triazole and 1-(but-3-ynyl)-1H benzo[d][1,2,3]triazole. 109(C) 2-(4-(Pyridin-2-yl)but-3-ynyl-2H-benzoFdl11,2,31triazole and 1-(4-(pyridin-2 yl)but-3-vnyl)-1H-benzord1[1,2,3]triazole The title compounds were prepared in accordance with the general method of Example 108(C), from 90 mg (0.53 mmol) of 2-(but-3-ynyl)-2H benzo[d][1,2,3]triazole and 1-(but-3-ynyl)-1H-benzo[d][1,2,3]triazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 10 mg (42 4mol, 8%) of 2-(4-(pyridin-2-yl)but-3-yny1)-2H-benzo[d][1,2,3]triazole as an orange oil with a purity of 82%. Another fraction yielded after SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH 4 0H 95:4:1 to 94:4:2) 19 mg (76 pimol, 14%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d][1,2,3]triazole as an orange oil. 2-(4-(Pyridin-2-yl)but-3-vnyl)-2H-benzoFdl[1,2,31triazole: LCMS (RT) : 3.49min; MS (ES+) gave m/z : 249.1. Rf (DCM/MeOH 98:2) = 0.2. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.31 (t, J=7.6, 2H), 5.01 (t, J=7.6, 2H), 7.19-7.24 (m, 1H), 7.35 (d, J=7.8, 1H), 7.41 (dd, J=3.1 and 6.6, 2H), 7.60-7.65 (m, 1H), 7.89 (dd, J=3.1 and 6.6, 2H), 8.56 (d, J=4.1, 1 H). 1-(4-(Pyridin-2-yl)but-3-ynyl)-1H-benzo[dll,2,31triazole: LCMS (RT) : 3.06min; MS (ES+) gave m/z : 249.1. Rf (DCM/MeOH 98:2)= 0.1. 1H-NMR (CDC1 3 ), 6 (ppm) : 3.17 (t, J=7.1, 2H), 4.93 (t, J=7.1, 2H), 7.17-7.23 (2H), 7.35-7.40 (m, 1H1), 7.46-7.51 (m, 1H), 7.57-7.62 (m, 1H), 7.65 (d, J=8.3, 1H), 8.08 (d, J=8.4, 1 H), 8.54 (d, J=4.6, 1H). Method B 2-(4-(Pvridin-2-y)but-3-ynyl)-2H-benzod]f1,2,31triazole hydrochloride 109(D) 2-(But-3-ynyl)-2H-benzoFdl1,2,3]triazole A solution of di-tert-butylazodicarboxylate (3.15 g, 13.4 mmol) in DCM (3 mL) was added dropwise over 30 min. at 0 0 C to a suspension of benzotriazole (2.40 g, 1.50 mmol), but-3-yn-1-ol (940 mg, 13.4 mmol) and polymer bounded triphenylphosphine (4.40 g, 16.8 mmol, 3mmol/g) in DCM (3 mL). The reaction mixture was stirred at room temperature with a polymix agitation for 2 days and filtered through celite. The organic phase was washed with NH40H, brine, dried over MgS04, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 571 mg (3.33 mmol, 25%) of 2-(but-3-ynyl)-2H benzo[d][1,2,3]triazole as a yellow solid. LCMS (RT) : 3.73min; MS (ES+) gave n/z : 172.0.
WO 2005/123703 PCT/IB2005/002390 154 Rf (cyclohexane/AcOEt 9:1) = 0.3. 109(E) 2-(4-(Pyridin-2-yl)but-3-nvl)-2H-benzofd1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (92 mg, 0.58 mmol) and 2-(but-3-ynyl)-2H benzo[d][1,2,3]triazole (100 mg, 0.58 mmol). Reaction time: .3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 90 mg of 2-(4-(pyridin-2-yl)but-3-yny1)-2H-benzo[d][1,2,3]triazole. Rf (DCM/MeOH 99:1) = 0.1. 109(F) 2-(4-(Pyridin-2-v1but-3-Ynyl)-2H-benzo[dlF 1,2,3 Itriazole hydrochloride A solution of HC1 (0.8 N, 906 pLl) was added to a solution of 2-(4-(pyridin-2-yl)but-3 ynyl)-2H-benzo[d][1,2,3]triazole (90 mg) in dioxane (5 mL). The reaction mixture was cooled in the fridge for 1 hour. The resulting precipitate was filtered, washed with cold dioxane and diethyl ether and dried to yield 2-(4-(pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole hydrochloride (99 mg, 0.35 mmol, 60%) as a white solid. LCMS (RT) : 3.51min; MS (ES+) gave m/z : 249.2. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.46 (t, J=7.0, 2H), 5.09 (t, J=7.0, 2H), 7.42 (dd, J=3.1 and 6.6, 2H), 7.66 (d, J=8.0, 1H), 7.72-7.78 (m, 1H), 7.89 (dd, J=3.1 and 6.6, 2H), 8.20-8.26 (m, IH), 8.72 (d, J=4.6, 1 H). Example 110 2-(4-(5-Phenvl-1H-pyrazol-1-y1)but-1 -ynyl)pyridine 110(A) 5-Phenvl-1-(4-trimethylsilanyl-but-3-vnyl)-lH-pyrazole and 5-phenyl-2-(4 trimethylsilanyl-but-3-vnvl)-2H-pyrazole The title compounds were prepared in accordance with the general method of Example 108(A), from 3-phenyl-1H-pyrazole (200 mg, 1.39 mmol) to yield 300 mg (1.12 mmol, 81%) of 5-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and 5 phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole. 110(B) 1-But-3-ynyl-5-phenyl-lH-pyrazole and 2-but-3-ynvl-5-phenvl-2H-pyrazole The title compounds were prepared in accordance with the general method of Example 108(B), from 5-phenyl-l-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and 5 phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole (300 mg, 1.12 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 29 mg (0.15 mmol, 13%) of 2-but-3-ynyl-5-phenyl-2H-pyrazole and 13 mg (66 pmol, 6%) of 1-but-3-ynyl-5-phenyl-lH-pyrazole. 110(C) 2-(4-(5-Phenyl-1H-pyrazol-1-yl)but-1-yny1)pyridine The title compound was prepared in accordance with the general method of Example 108(C), from 30 mg (0.15 mmol) of 2-but-3-ynyl-5-phenyl-2H-pyrazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 95:5, DCM/MeOH/NH40H 94:5:1 to 94:4:2) to yield 5 mg (18 hmol, 10%) of 2-(4-(5-phenyl-1H-pyrazol-1-y1)but-1-yny1)pyridine as a yellow solid. LCMS (RT) : 3.86min; MS (ES+) gave m/z: 274.1. Rf (DCM/MeOH 98:2)= 0.2.
WO 2005/123703 PCT/IB2005/002390 155 1 H-NMR (DMSO[D] 6 ), 8 (ppm) : 3.01 (t, J=6.7, 2H), 4.39 (t, J=6.7, 2H), 6.70 (d, J=2.3, 1H), 7.25-7.29 (in, 1H), 7.30-7.35 (m, 1H), 7.36-7.41 (3H), 7.72-7.77 (n, 1H), 7.78-7.80 (2H), 7.87 (d, J=2.3, 1H), 8.48-8.51 (m, 1H). Example 111 2-(4-(3-Phenylisoxazol-5-v)but-1-vnvllpyridine 111(A) 3 -Phenyl-5-(4-trimethylsilanyl-bt-3-nyl)-isoxazole The title compound was prepared in accordance with the general method of Example 107(B), from 5-chloromethyl-3-phenyl-isoxazole (200 mg, 1.03 mmol, reaction time: 1 day), to yield 3-phenyl-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (127 mg, 0.47 mmol, 45%) as a white solid. LCMS (RT) : 5.59min; MS (ES+) gave m/z : 270.1. 111(B) 5-But-3-ynyl-3-phenyl-isoxazole The title compound was prepared in accordance with the general method of Example 108(B), from 3-phenyl-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (127 mg, 0.47 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 67 mg (0.34 mmol, 72%) of 5-but-3-ynyl-3-phenyl-isoxazole as a brown solid. 111(C) 2-(4-(3-Phenylisoxazol-5-1)but-1-vyl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (70 mg, 0.34 mmol) and 5-but-3-ynyl-3-phenyl-isoxazole (67 mg, 0.34 mmol). Reaction time: 24 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 70 mg (0.26 mmol, 75%) of 2-(4-(3 phenylisoxazol 5-yl)but-1-ynyl)pyridine as a brown solid. LCMS (RT) : 4.18min; MS (ES+) gave m/z : 275.1. 1 H-NMR (CDC1 3 ), 6 (ppm) : 2.91 (t, J=7.4, 2H), 3.17 (t, J=7.4, 2H), 6.49 (s, 1H), 7.19-7.23 (m, 1H), 7.35-7.39 (m, 1H), 7.41-7.48 (3H), 7.60-7.65 (m, 1H), 7.77-7.83 (2H), 8.54-8.58 (m, 1 H). Example 112 2-(4-(2-Methylthiazol-4-l)but-3-ynl)benzofdlthiazole The title compound was prepared in accordance with the general method of Example 1, from 4-iodo-2-methyl-thiazole (120 mg, 0.53 mmol) and 2-but-3-ynyl benzo[d]thiazole (100 mg, 0.53 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 152 mg (0.28 mmol, 53%) of 2-(4-(2-methylthiazol-4-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid. LCMS (RT) : 4.33min; MS (ES+) gave m/z : 285.1. Rf (cyclohexane/AcOEt 4:1) = 0.2. H-NMR (CDC1 3 ), 6 (ppm) : 2.70 (s, 3H), 3.02 (t, J=7.5, 2H), 3.44 (t, J=7.5, 2H), 7.22 (s, 1H), 7.35-7.40 (m, 1H), 7.45-7.50 (m, 1H), 7.86 (dd, J=0.5 and 8.0, 1H), 8.09 (d, J=8.0, 1H).
WO 2005/123703 PCT/IB2005/002390 156 Example 113 2-(4-(5-Fluoropyridin-2-yl)but-3-ynvllbenzo[dlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoro-pyridine (103 mg, 0.59 mmol) and 2-but-3-ynyl benzo[d]thiazole (110 mg, 0.59 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 78 mg (0.28 mmol, 47%) of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid. LCMS (RT) : 4.36min; MS (ES+) gave m/z : 283.1. Rf (cyclohexane/AcOEt 4:1) = 0.2. 'H-NMR (CDCl 3 ), 8 (ppm) : 3.05 (t, J=7.4, 2H), 3.46 (t, J=7.4, 2H), 7.32-7.41 (3H), 7.45-7.50 (m, 1H), 7.87 (dd; J=0.5 and 8.1, 1H), 8.00 (d, J=8.1, 1H), 8.41 (d, J=2.8, 1H). Example 114 2-(4-(6-Methylpyridin-2-v)but-3-ynl)benzordlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methyl-pyridine (110 mg, 0.64 mmol) and 2-but-3-ynyl benzo[d]thiazole (120 mg, 0.64 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 122 mg (0.44 mmol, 68%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a beige solid. LCMS (RT) : 3.53min; MS (ES+) gave m/z : 279.1. Rf (cyclohexane/AcOEt 7:3) = 0.2. 1 H-NMR (CDC1 3 ), 6 (ppm) : 2.55 (s, 3H), 3.04 (t, J=7.4, 2H), 3.46 (t, J=7.4, 2H), 7.08 (d, J=7.8, 1H), 7.21 (d, J=7.7, 1H), 7.35-7.40 (m, 111), 7.45-7.49 (m, 1H), 7.50-7.53 (m, 1H), 7.86 (d, J=8.0, 1H), 8.00 (d, J=8.0, 1H). Example 115 2-(4-(6-Chloropyridin-2-l)but-3-ynllbenzofdithiazole The title compound was prepared in accordance with the general method of Example 108(C), from 2,6-dichloro-pyridine (395 mg, 2.67 mmol) and 2-but-3-ynyl benzo[d]thiazole (100 mg, 0.53 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 31 mg (0.10 mmol, 19%) of 2-(4-(6-chloropyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a white solid. LCMS (RT) : 4.73min; MS (ES+) gave m/z: 299.1, 301.0. Rf (cyclohexane/AcOEt 4:1) = 0.2. 'H-NMR (CDCl 3 ), S (ppm).: 3.05 (t, J=7.5, 2H), 3.45 (t, J=7.5, 2H), 7.25 (dd, J=0.7 and 8.0, 1H), 7.30 (dd, J=0.7 and 7.6, 1H), 7.36-7.41 (m, 1H), 7.46-7.50 (m, 1H), 7.56-7.61 (m, 1H), 7.85-7.89 (m, 1H), 8.00 (d, J=8.1, 1H).
WO 2005/123703 PCT/IB2005/002390 157 Example 116 7-Chloro-4-fluoro-2-(4-(pyridin-2-v1)but-3-yn benzo[dlthiazole 116(A) 2-Amino-6-chloro-3-fluoro-benzenethiol The title compound was prepared in accordance with the general method of Example 100(A), from 7-chloro-4-fluoro-benzothiazol-2-ylaine (1.1 g, 5.4 mmol) to yield 2 amino-6-chloro-3-fluoro-benzenethio1 (350 mg, 1.97 mmol, 36%) as an orange oil. 116(B) 2-But-3- vnyl-7-chloro-4-fluoro-benzo[dlthiazole The title compound was prepared in accordance with the general method of Example 8(A), from 2-amino-6-chloro-3-fluoro-benzenethiol (350 mg, 1.97 mmol). Reaction time: 2 days. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 100 mg (0.42 mmol, 21%) of 2-but-3-ynyl-7 chloro-4-fluoro-benzo[d]thiazole as an orange oil. LCMS (RT) : 4.88min; MS (ES+) gave m/z : 240.1. 116(C) 7-Chloro-4-fluoro-2-(4-(pyridin-2-v1)but-3-ynyllbenzordlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-7-chloro-4-fluoro benzo[d]thiazole (100 mg, 0.42 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 15 mg (47 ptmol, 11%) of 7 chloro-4-fluoro-2-(4-(pyridin-2-y1)but-3-ynyl)benzo[d]thiazole as a brown oil. LCMS (RT) : 4.59min; MS (ES+) gave m/z: 317.1, 31 9 .1. Rf (cyclohexane/AcOEt 7:3)= 0.2. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.07 (t, J=7.3, 2H), 3.49 (t, J=7.3, 2H), 7.16 (dd, J=8.6 and 9.8, 1H), 7.20-7.25 (m, 1H), 7.32 (dd, J=3.8 and 8.6, 1H), 7.38-7.42 (in, 1H), 7.61-7.68 (in, 1H), 8.57 (s, 1H). Example 117 2-(4-(6-Fluoropyridin-2-yl)but-3-ynyl)benzoFdlthiazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-fluoro-pyridine (66 mg, 0.37 mmol) and 2-but-3-ynyl benzo[d]thiazole (70 mg, 0.37 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 31 mg (0.11 mmol, 29%) of 2-(4-(6-fluoropyridin-2-yl)but- 3 -ynyl)benzo[d]thiazole as a white solid. LCMS (RT) : 4.51min; MS (ES+) gave m/z : 283.1. Rf (cyclohexane/AcOEt 7:3)= 0.2. 'IH-NMR (CDC1 3 ), S (ppm) : 3.05 (t, J=7.5, 2H), 3.46 (t, J=7.5, 2H), 6.87 (dd, J=2.4 and 8.2, 1H), 7.26 (d, J=1.6, 1H), 7.36-7.41 (m, 1H), 7.46-7.50 (in, lH), 7.68-7.75 (m, 1H), 7.85-7.88 (m, 1H), 8.00 (d, J=8.1, 1H). Example 118 2-(4-(Pyrdin-2-v1tyl-3-yny1)guinoline 118(A) 2-(4-Trimegthylsilanvl-but-3-3yv)-guinoline WO 2005/123703 PCT/IB2005/002390 158 2-Methyl-quinoline (0.28 mL, 2.09 mmol) was added dropwise to a solution of LDA (3.0 mL, 0.8 M in THF) in THF (3 mL) at -78 0 C and the reaction mixture was stirred for 1 hourat -78'C. Then (3-bromo-prop-1-ynyl)-trimethyl-silane (0.39 mL, 2.51 mmol) was added to the reaction mixture, the solution was stirred for 18 hours at room temperature and was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over MgS04, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 338 mg (1.33 mmol, 64%) of 2-(4-trimethylsilanyl but-3-ynyl)-quinoline as a yellow solid. LCMS (RT) : 3.93min; MS (ES+) gave m/z : 254.2. 118(B) 2-But-,3-ynyl-quinoline The title compound was prepared in accordance with the general method of Example 108(B), from 2-(4-trimethylsilanyl-but-3-ynyl)-quinoline (803 mg, 3.17 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 94:6 to 90:10) to yield 419 mg (2.31 mmol, 73%) of 2-but-3-ynyl-quinoline as a yellow liquid. LCMS (RT) : 2.29min; MS (ES+) gave m/z : 182.1. 118(C) 2-(4-(Pyridin-2-yl)but-3-ynyl)quinoline The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (87 mg, 0.55 mmol) and 2-but-3-ynyl-quinoline (100 mg, 0.55 mmol). Reaction time: 120'C for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 74 mg (0.29 mmol, 52%) of 2-(4-(pyridin-2-yl)but-3-ynyl)quinoline as a yellow oil. LCMS (RT) : 2.56min; MS (ES+) gave m/z : 259.2. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.02 (t, J=7.5, 2H), 3.34 (t, J=7.5, 2H), 7.17-7.21 (m, 1H), 7.33 (d, J=7.8, 1H), 7.43 (d, J=8.4, 1H), 7.49-7.54 (in, 1H), 7.58-7.63 (in, 1H), 7.69-7.74 (m, 1H), 7.81 (d, J=8.1, 111), 8.08 (d, J=8.4, 1H), 8.12 (d, J=8.4, 1H), 8.55 (d, J=4.7, 1H). Example 119 2-(5-(Pyridin-2-v1)pent-4-vnvl-2H-benzoFd1l ,2,3|triazole 119(A) 5-Pyridin-2-yl-pent-4-yn-1-ol The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (4.46 g, 28.2 mmol) and pent-4-yn-l-ol (2.50 g, 29.7 mmol). Reaction time : 14 hours. The crude residue was purified by flash chromatography (DCM/MeOH 97:3) to yield 4.00 g (24.8 mmol, 88%) of 5-pyridin-2-yl-pent-4-yn-1 ol as a brown oil. 119(B) 2-(5-Bronio-pent-1-ynyl)-pyridine Br 2 (1.11 mL, 21.4 mmol) was added to a solution of triphenylphosphine (8.30 g, 30.7 mmol) in DCM (40 mL) at -5'C. A solution of 5-pyridin-2-yl-pent-4-yn-1-ol (3.00, 18.6 mmol) in DCM (10 mL) was added dropwise to the reaction mixture in order to maintain a temperature lower than 5'C. The reaction mixture was stirred for 5 hours at -10 C and was quenched with a saturated solution of NaHC0 3 . The aqueous phase was extracted with DCM. The resulting organic phase was washed with brine, dried over MgS04, filtered and evaporated. The crude residue was purified by flash WO 2005/123703 PCT/IB2005/002390 159 chromatography (DCM/MeOH 99.5:0.5) to yield 2-(5-bromo-pent-1-yny1)-pyridine (1.20 g, 5.35 mmol, 29%) with a purity of 50%. 119(C) 2-(5-(Pyridin-2-v1)pent-4-vnvl)-2H-benzo[dl[L2,31triazole and 1-(5-pyridin 2-v1)pent-4-ynv1)-1H-benzordl[1,2,31triazole The title compounds were prepared in accordance with the general method of Example 108(A), from 2-(5-bromo-pent-1-ynyl)-pyridine (298 mg, 0.66 mmol) and benzotriazole (72 mg, 0.60 mmol). The crude product was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 2-(5-(pyridin-2-yl)pent-4-ynyl) 2H-benzo[d][1,2,3]triazole (27 mg, 0.1 mmol) as an orange oil and 1-(5-(pyridin-2 yl)pent-4-ynyl)-lH-benzo[d][1,2,3]triazole (27 mg, 0.1 mmol) as an orange solid. 2-(5-(pyridin-2-yl)pent-4-ynyl)-2H-benzo[d][1,2,3]triazole LCMS (RT) : 3.46min; MS (ES+) gave m/z : 263.2. Rf (DCM/MeOH 98:2) = 0.2. 1 H-NMR (CDC1 3 ), 5 (ppm) : 2.43-2.50 (2H), 2.58 (t, J=6.8, 2H), 4.93 (t, J=6.8, 2H), 7.18-7.22 (m, 1H), 7.33-7.36 (m, 1H), 7.39 (dd, J=3.1 and 6.6, 2H), 7.59-7.64 (m, 1H), 7.87 (dd, J=3.1 and 6.6, 2H), 8.53-8.56 (m, 1H). 1-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzo[d][1,2,3]triazole LCMS (RT) : 3.14min; MS (ES+) gave m/z : 263.2. Rf (DCM/MeOH 98:2) = 0.1. 'H-NMR (CDC1 3 ), 6 (ppm) : 2.37-2.41 (2H), 2.52 (t, J=6.7, 2H), 4.85 (t, J=6.7, 2H), 7.21-7.25 (m, 1H), 7.35-7.40 (2H), 7.46-7.51 (in, 1H), 7.62-7.66 (2H), 8.04-8.08 (m, 1H), 8.58 (d, J=4.4, 111). Example 120 2-(4-(6-(Fluoromethyl)pridin-2-1)but-3-vnvl)-[1,2,41triazolo[4,3-alpyridin-3(2H) one The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (70 mg, 0.37 mmol, Example 39(A)) and 2-bromo-6-(fluoromethyl)pyridine (78 mg, 0.41 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 20 mg (67 .mol, 18%) of 2-(4-(6-(fluoromethyl)pyridin-2-y)but-3-ynyl) [1,2,4]triazolo[4,3-alpyridin-3(2H)-one as an orange solid (M.P. = 106-107 0 C). LCMS (RT) : 3.08min; MS (ES+) gave m/z: 297.0. Rf (DCM/MeOH 98:2) = 0.05. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.00 (t, J=7.2, 2H), 4.29 (t, J=7.2, 2H), 5.36-5.54 (m, 2H), 6.46-6.52 (m, 1H), 7.09 (dd, J=1.2 and 3.6, 2H), 7.33 (d, J=7.8, 1H), 7.38 (d, J=7.8, 1H), 7.66-7.72 (m, 1H), 7.73-7.78 (m, 1H). Example 121 2-(4-(1-Methyl11H-pyrazol-3-yllbut-3-yn1)benzo[dlthiazole The title compound was prepared in accordance with the general method of Example 108(C), from 3-bromo-1-methyl-IH-pyrazole (100 mg, 0.62 mmol) and 2-but-3-ynyl benzo[d]thiazole (233 mg, 1.24 mmol, Example 35(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 35 mg (0.13 WO 2005/123703 PCT/IB2005/002390 160 mmol, 21%) of 2-(4-(I-methyl-1H-pyrazol-3-yl)but- 3 -ynyl)benzo[d]thiazole as a brown semi-solid. LCMS (RT) : 3.96min; MS (ES+) gave m/z : 268.1. Rf (cyclohexane/AcOEt 7:3) = 0.2. Example 122 2-(4-(4-Phenvl-H-pyrazol-1-v1)but-1-vyvlpyridine 122(A) 4-Phenyl- 1 -(4-trimethylsilanvl-but-3 -ynv)-lH-pyrazole The title compound was prepared in accordance with the general method of Example 108(A), from 4-phenyl-1H-pyrazole (250 mg, 1.73 mmol) to yield 380 mg (1.42 mmol, 82%) of 4-phenyl-l-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole. 122(B) 1-But-3-ynvl-4-phenyl-1H-pyrazole The title compound was prepared in accordance with the general method of Example 108(B), from 4-phenyl-1-(4-trimethylsilanyl-but-3-yny)-1H-pyrazole (380 mg, 1.42 mmnol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 80 mg (0.41 mmol, 29%) of 1-but-3-ynyl-4-phenyl-1H-pyrazole. 122(C) 2-(4-(4-Phenyl-1H-pyrazol-1-vl)but-1-ynvl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 80 mg (0.41 mmol) of 1-but-3-ynyl-4-phenyl-lH-pyrazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) and SCX column (DCM, DCM/MeOH 97:3, DCM/MeOH/NH40H 94:5:1) to yield 2 mg (7 ptmol, 2%) of 2-(4-(4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine. LCMS (RT) : 3.76min; MS (ES+) gave m/z : 274.1. Rf (DCM/MeOH 98:2)= 0.3. Example 123 7-Chloro-2-(4-(pvyridin-2-yl)but-3-vnLy)-2H-indazole 123(A) 7-Chloro-lH-indazole A solution of 2-chloro-6-methy-phenylamine (500 mg, 3.53 mmol) in H 2
SO
4 (1.37 mL) was diluted by adding over 15 min. 2 mL of water in order to maintain a temperature below 901C. Then the reaction mixture was cooled to 5-10'C and a solution of sodium nitrite (246 mg, 3.57 mmol) in water (1 mL) was added over 2 hours. The resulting diazonium solution was then added to a solution of sodium acetate (5.21 g, 63.6 nmmol) in water (20 mL) at a temperature maintained between 65 to 75 'C. The resulting precipitate was filtered and treated with a solution of NaOH (6.00 g) in water (100 mL) at 95-100'C. The aqueous phase was separated while hot from the small amount of black tarry by-products, cooled to 50-60'C and acidified with HC1 (37%, 12.5 mL). The reaction mixture was cooled down to room temperature, the resulting precipitate was filtered, was washed thrice with cold water and was dried under vacuum to yield 7-chloro-1H-indazole (220 mg, 1.44 mmol, 41%) as a white solid.
WO 2005/123703 PCT/IB2005/002390 161 123(B) 7-hloro-2-(4-trimethylsilanyl-but-3-ynvl)-2H-indazole and 7-chloro-l-(4 trimethvisilanL-but-3 -nyl)-1H-indazole The title compounds were prepared in accordance with the general method of Example 108(A), from 7-chloro-1iH-indazole (220 mg, 1.44 mmol) to yield 250 mg (0.90 mmol, 63%) of 7-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 7 chloro-1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole. 123(C) 2-But-3-ynyl-7-chloro-2H-indazole The title compound was prepared in accordance with the general method of Example 108(B), from 7-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 7-chloro-1 (4-trimethylsilanyl-but-3-yny)-1H-indazole (250 mg, 0.90 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 44 mg (0.21 mmol, 23%) of 2-(but-3-ynyl)-7-chloro-2H-indazole as an orange oil. 123(D) 7-Chloro-2-(4-(pyridin-2-l)but-3-nyl-2H-idazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (36 mg, 0.23 mmol) and 2-but-3-ynyl-7-chloro-2H-indazole (44 mg, 0.21 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 11 mg (41 pmol, 19%) of 7-chloro-2-(4 (pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown oil. Rf (DCM/MeOH 98:2)= 0.05. LCMS (RT) : 4.13min; MS (ES+) gave m/z : 282.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.06 (t, J=7.5, 2H), 5.07 (t, J=7.5, 2H), 7.05-7.10 (m, 1H), 7.18-7.22 (m, 1H), 7.27-7.30 (m, 1H), 7.37 (dd, J=0.9 and 7.5, 1H), 7.58-7.63 (m, 1H), 7.64 (dd, J=0.9 and 8.0, 1H), 8.04 (s, 1H), 8.52-8.56 (m, 1H). Example 124 2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-benzord]1,2,31triazole 124(A) 6-Pyridin-2-yl-hex-5-yn-1-ol The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (6.44 g, 40.8 mmol) and hex-5-yn-1-ol (4.00 g, 40.8 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 1:1) to yield 5.56 g (31.7 mmol, 78%) of 6-pyridin-2-yl-hex-5-yn-l-ol as an orange oil. 124(B) 2-(6-Bromo-hex-1-vnyl)-pyridine The title compound was prepared in accordance with the general method of Example 119(B), from 6-pyridin-2-yl-hex-5-yn-1-ol (1.00 g, 5.77 nmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 2-(6-bromo hex-1-ynyl)-pyridine (0.74 g, 3.10 mmol, 54%) as an orange oil. LCMS (RT) : 3.94nin; MS (ES+) gave m/z : 240.2. 124(C) 1-(6-(Pyridin-2-yl)hex-5-vnyl)-1H-benzoPdl[1,2,31triazole and 2-(6-(pyridin 2-vl)hex-5-vnvl)-2H-benzord1[1,2,31triazole The title compounds were prepared in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol) and benzotriazole (125 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 2-(6-(pyridin-2-yl)hex-5-ynyl) 2H-benzo[d][1,2,3]triazole (38 mg, 0.14 mol, 13%) as a brown oil and WO 2005/123703 PCT/IB2005/002390 162 (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-l1H benzo[d][l,2,3]triazole (48 mg, 0.17 mmol, 16%) as a brown oil. 2-(6-(Pyridin-2-y)hex-5-ynvl)-2H-benzo[d1[1,2,31triazole: LCMS (RT) : 3.93min; MS (ES+) gave m/z : 277.2. Rf (DCM/MeOH 98:2) = 0.2. 'H-NMR (CDC1 3 ), S (pm) : 1.68-1.73 (2H), 2.30-2.36 (2H), 2.53 (t, J=7.0, 2H), 4.81 (t, J=7.0, 2H), 7.19 (ddd, J=1.1, 4.9 and 7.6, 1H), 7.34-7.41 (3H), 7.59-7.64 (m, 1H), 7.84-7.89 (2H), 8.55 (d, J=4.3, 1H). 1-(6-(Pyridin-2-yl)hex-5-nvy)-1H-benzo[d1,2,31triazole: LCMS (RT) : 3.43min; MS (ES+) gave m/z : 277.2. Rf (cyclohexane/AcOEt 1:1) = 0.2. 'H-NMR (CDC1 3 ), S (ppm) : 1.65-1.
7 3 (2H), 2.21-2.28 (2H), 2.53 (t, J=7.0, 2H), 4.72 (t, J=7.0, 2H), 7.20 (ddd, J=1.1, 4.9 and 7.6, 1H), 7.34 (d, J=7.8, 1H), 7.35-7.40 (m, 1H), 7.45-7.50 (m, 1H), 7.54-7.68 (n, 1H), 7.59-7.64 (m, 1H), 8.05-8.09 (m, 1H), 8.55 (d, J=4.4, 1H). Example 125 2-(6-(Pyridin-2-yl)hex-5-ynyl)-2H-indazole The title compounds were prepared in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol, Example 124(B)) and indazole (124 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 2-(6-(pyridin-2-yl)hex 5-ynyl)-2H-indazole (26 mg, 94 pimol, 9%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-l1H-indazole (15 mg, 54 ptmol, 5%) as a brown oil. 2-(6-(Pyridin-2-yl)hex-5-vnly)-2H-indazole: LCMS (RT) : 3.93mM; MS (ES+) gave m/z : 276.2. Rf (cyclohexane/AcOEt 1:1) = 0.3. 'H-NMR (CDC1 3 ), S (ppm) : 1.62-1.
69 (2H), 2.11-2.18 (2H), 2.49 (t, J=7.0, 2H), 4.46 (t, J=7.0, 2H), 7.12-7.17 (m, 1H), 7.19 (ddd, J=1.1, 4.9 and 7.6, 1H), 7.32-7.35 (m, 1H), 7.35-7.39 (m, 1H), 7.44 (dd, J=0.9 and 8.5, 1H), 7.58-7.63 (m, 1H), 7.72-7.76 (m, 1H), 8.00 (d, J=0.9, 11), 8.52-8.56 (m, 1H). 1-(6-(Pyridin-2-v1)hex-5-vnyvl-1H-indazole: LCMS (RT) : 3.54min; MS (ES+) gave m/z: 276.2. Rf (cyclohexane/AcOEt 1:1) = 0.2. 'H-NMR (CDC1 3 ), S (ppM) : 1.64-1.
7 1 (2H), 2.20-2.27 (2H), 2.51 (t, J=7.0, 21), 4.50 (t, J=7.0, 2H), 7.09 (ddd, J=0.8, 6.6 and 8.4, 1H), 7.20 (ddd, J=1.1, 4.9 and 7.6, 1H), 7.28-7.31 (m, 1H), 7.36 (d, J=7.6, 1H), 7.59-7.64 (m, 1H), 7.64-7.67 (m, 1H), 7.70 7.73 (m, 1H), 7.95 (d, J=0.8, 1H), 8.55 (d, J=4.3, 1H). Example 126 2-(4-(6-(Fluoromethllpridin-2-y1)but-3 -vny1)uinoline The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (157 mg, 0.83 mmol) and 2-but-3 ynyl-quinoline (150 mg, 0.83 mmol, Example 118(B)). Microwave conditions: 120'C for 15 minutes. The crude residue was purified by flash chromatography WO 2005/123703 PCT/IB2005/002390 163 (cyclohexane/AcOEt 4:1) to yield 127 mg (0.44 mmol, 53%) of 2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoline as an orange solid (M.P. = 70.2 74.3-C). LCMS (RT) : 2.98min; MS (ES+) gave m/z: 291.2. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.03 (t, J=7.5, 2H), 3.33 (t, J=7.5, 2H), 5.40-5.53 (m, 2H), 7.29 (d, J=7.8, 1H), 7.38 (d, J=7.8, 1H), 7.40 (d, J=8.4, 1H), 7.49-7.54 (m, 1H), 7.65-7.70 (m, 1H), 7.70-7.74 (in, 111), 7.81 (d, J=8.1, 1H), 8.07 (d, J=8.4, 1H), 8.11 (d, J=8.4, 1H). Example 127 5-Fluoro-2-(4-(pyridin-2-y)but-3-ynl)-2H-benzo d1[1,2,31triazole 127(A) 5-Fluoro-1H-benzordll,2,31triazole A solution of sodium nitrite (284 mg, 4.12 mmol) in water (1 mL) was added to a solution of 4-fluoro-benzene-1,2-diamine (520 mg, 4.12 mmol) in acetic acid (0.50 mL) and water (2.50 mL) at 0 0 C. The reaction mixture was stirred for few minutes at 50'C and 1 hour at 0 0 C. The precipitate was filtered, washed with cold water and dried to yield 5-fluoro-1H-benzo[d][1,2,3]triazole (565 mg, 3.50 mmol, 85%). 127(B) 5-Fluoro-2-(4-trimethylsilanyl-but-3-yny1)-2H- benzofd1l,2,31triazole (4-Bromo-but-1-ynyl)-trimethyl-silane (294 mg, 1.43 mmol) was added to a solution of 5-fluoro-1H- benzo[d][1,2,3]triazole (187 mg, 1.36 mmol) in a solution of NaOH (2N, 955 pL). The reaction mixture was heated at 100 0 C for 14 hours, then it was cooled down and was extracted with DCM. The organic phase was washed with water, brine, dried over MgSO 4 , filtered and evaporated to yield 355 mg (1.36 mmol) 5-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole including the two others isomers. 127(C) 2-But-3-ynyl-5-fluoro-2H-benzord1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 108(B), from 5-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-benzo[d][1,2,3]triazole (355 mg, 1.36 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 27 mg (0.14 mmol, 10%) of 2-(but-3-ynyl)-5 fluoro-2H-benzo[d] [1,2,3]triazole. Rf (cyclohexane/AcOEt 9:1) = 0.3. 127(D) 5-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzofd1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (20 mg, 0.13 mmol) and 2-(but-3-ynyl)-5-fluoro-2H benzo[d][1,2,3]triazole (24 mg, 0.13 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2 to DCM/MeOH/NH 4 0H 95:4:1) to yield 7.6 mg (26 pmmol, 21%) of 5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 97:3) = 0.2. LCMS (RT) : 3.71min; MS (ES+) gave ml/z: 267.2. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.29 (t, J=7.5, 211), 4.97 (t, J=7.5, 2H), 7.18-7.24 (2H), 7.32-7.36 (m, 1H), 7.47 (ddd, J=0.6, 2.4 and 8.7, 1H), 7.59-7.65 (m, 1H), 7.86 (ddd, J=0.6, 4.8 and 9.3, 1H), 8.53-8.57 (i, 1H).
WO 2005/123703 PCT/IB2005/002390 164 Example 128 2-(4-(6-Methv pyridin-2-v1)but-3-vnvl)quinoline The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-methyl-pyridine (209 mg, 1.21 mmol) and 2-but-3-ynyl quinoline (220 mg, 1.21 mmol Example 118(B)). Microwave conditions: 120'C for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 98 mg (0.36 mmol, 30%) of 2-(4-(6-methylpyridin 2-yl)but-3-ynyl)quinoline as a yellow oil. LCMS (RT) : 2.44min; MS (ES+) gave m/z : 273.2. 1 H-NMR (CDC1 3 ), 5 (ppm) : 2.54 (s, 3H), 3.01 (t, J=7.5, 2H), 3.32 (t, J=7.5, 2H), 7.05 (d, J=7.7, 1H), 7.15 (d, J=7.7, 1H), 7.41 (d, J=8.4, 1K), 7.46-7.50 (in, 1H), 7.49-7.54 (in, 1H), 7.68-7.73 (m, 1H), 7.78-7.82 (in, 1H), 8.07 (d, J=8.4, 1H),'8.11 (d, J=8.4, 1H). Example 129 2-(4-(6-(Fluoromethvl)pyridin-2-yl)but-3-ynyl)quinoxaline 129(A) 2-(4-Trimethylsilanyl-but-3-vnyl)-quinoxaline The title compound was prepared in accordance with the general method of Example 118(A), from 2-methyl-quinoxaline (0.47 mL, 3.47 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 291 mg (1.11 mmol, 32%) of 2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orange oil. LCMS (RT) : 5.16min; MS (ES+) gave m/z : 255.1. 129(B) 2-But-3-ynvl-quinoxaline The title compound was prepared in accordance with the general method of Example 108(B), from 2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (291 mg, 1.11 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 94:6 to 90:10) to yield 120 mg (0.66 mmol, 71%) of 2-but-3-ynyl-quinoxaline as a yellow liquid. LCMS (RT) : 3.59min; MS (ES+) gave m/z : 183.1. 129(C) 2-(4-(6-(Fluoromethyllpvridin-2-yl)but-3-vnvl)quinoxaline The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (104 mg, 0.55 mmol) and 2-but-3 ynyl-quinoxaline (100 mg, 0.55 mmol). Microwave conditions: 120'C for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 116 ing (0.40 mmol, 72%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 ynyl)quinoxaline as an orange solid (M.P.: 136'C dec.). LCMS (RT) : 3.96min; MS (ES+) gave m/z : 292.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.06 (t, J=7.4, 2H), 3.37 (t, J=7.4, 2H), 5.40-5.53 (m, 2H), 7.26-7.30 (m, 1H), 7.39 (d, J=7.8, 1H), 7.66-7.71 (in, 1K), 7.72-7.81 (2K), 8.06 8.12 (2H), 8.86 (s, 1H).
WO 2005/123703 PCT/IB2005/002390 165 Example 130 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo d1l.2,31triazole hydrochloride 130(A) 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynv)-2H-benzordl[1,2,3]triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (111 mg, 0.58 mmol, Example 190(E)) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 61 mg (0.22 mmol, 37%) of 2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid. Rf (DCM/MeOH 98:2) = 0.2. LCMS (RT) : 4.06min; MS (ES+) gave m/z : 281.1. 1 H-NMR , CDC1 3 , 6 (ppm) : 3.31 (t, J=7.5, 2H), 5.00 (t, J=7.5, 2H), 5.40-5.53 (m, 2H), 7.29 (d, J=7.8, 11), 7.39-7.43 (3H), 7.68-7.72 (m, 1H), 7.88 (dd, J=3.0 and 6.6, 2H). 130(B) 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynvl)-2H-benzo[dl[l,2,3]triazole hydrochloride The title compound was prepared in accordance with the general method of Example 109(F), from 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole (60 mg, 0.21 mmol) to yield 2-(4-(6-(fluoromethyl)pyridin-2 yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole hydrochloride (33 mg, 0.11 mmol, 48%) as a white solid (M.P.: 172.5-173.5'C). LCMS (RT) : 4.08min; MS (ES+) gave m/z: 281.2. 1 H-NMR CDC1 3 , 5 (ppm) : 1.72-2.80 (br. s, 1H), 3.36 (t, J=7.0, 2H), 5.03 (t, J=7.0, 2H), 5.64-5.78 (m, 2H), 7.38-7.42 (3H), 7.58 (d, J=8.0, 1H), 7.87 (dd, J=3.0 and 6.5, 2H), 7.89-7.94 (in, 1H). Example 131 4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H benzoldf1,2,3]triazole hydrochloride 131(A) 5,7-Difluoro-1H-benzodl [1,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3,5-difluorobenzene-1,2-diamine (520 mg, 3.61 mmol) to yield 5,7 difluoro-lH-benzo[d][1,2,3]triazole (492 mg, 3.17 mmol, 88%) as a dark solid. 131(B) 2-(But-3-ynyl)-4,6-difluoro-2H-benzofdl[1,2,3]triazole The title compound was prepared in accordance with the general method of Example 109(D), from 5,7-difluoro-1H-benzo[d][1,2,3]triazole (271 mg, 1.75 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 33%) of 2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole. Rf (DCM/MeOH 9:1) = 0.3. 131(C) 4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-vl)but-3-vnv1)-2H benzol dl El,2,31triazole WO 2005/123703 PCT/IB2005/002390 166 The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and 2-(but-3-ynyl) 4,6-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mol, 53%) of 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 ynyl)-2H-benzo[d][1,2,3]triazole as a brown oil. Rf (DCM/MeOH 98:2) = 0.2. LCMS (RT) : 4.44min; MS (ES+) gave m/z: 317.1. 'H-NMR , 5 (ppm) : 3.31 (t, J=7.3, 2H), 4.99 (t, J=7.3, 2H), 5.42 (s, 1H), 5.51 (s, 1H), 6.89-6.95 (m, 111), 7.28-7.33 (2H), 7.41 (d, J=7.8, 1H), 7.68-7.73 (m, 1H). 131 (D) 4,6-Difluoro-2-(4-(6-(fluoromethvl)pyridin-2-vl)but-3- ny)-2H benzodll,2,31triazole hydrochloride The title compound was prepared in accordance with the general method of Example 109(F), from 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole (45 mg) to yield the corresponding hydrochloride (50 mg, 0.14 mmol) as a white solid (M.P.: 128-130'C). LCMS (RT) : 4.46min; MS (ES+) gave m/z : 317.1. 'H-NMR , 6 (ppm) : 3.40 (t, J=7.1, 2H), 5.07 (t, J=7.1, 2H), 5.40-5.53 (m, 211), 6.89 6.95 (m, 1H), 7.31 (dd, J=2.0 and 8.2, 1H), 7.54 (d, J=7.9, 1H), 7.74 (d, J=7.9, 1H), 8.08-8.13 (m, 1H). Example 132 4,5-Difluoro-2-(4-(6-(fIuoromethv1)pyridin-2-yl)but-3-yny1)-2H benzo[d]l,2,3]triazole hydrochloride 132(A) 4,5-Difluoro-1H-benzod]El,2,3]triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3,4-difluorobenzene-1,2-diamine (490 mg, 3.40 mmol) to yield 4,5 difluoro-1H-benzo[d][1,2,3]triazole (485 mg, 3.13 mmol, 92%). 132(B) 2-(But-3-vnvl)-4,5-difluoro-2H-benzodlF1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 4,5-difluoro-lH-benzo[d][1,2,3]triazole (266 mg, 1.71 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 34%) of 2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole. Rf (DCM/MeOH 9:1) = 0.2. 132(C) 4,5-Difluoro-2-(4-(6-(fluoromiethvl)pyridin-2-vl)but-3-ynyl)-2H benzo[d]l[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and 2-(but-3-ynyl) 4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mmol, 59%) of 4,5-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 ynyl)-2H-benzo[d][1,2,3]triazole. Rf (DCM/MeOH 98:2) = 0.2. LCMS (RT) : 4.43min; MS (ES+) gave m/z: 317.1.
WO 2005/123703 PCT/IB2005/002390 167 1 H-NMR , 8 (ppm) : 3.31 (t, J=7.3, 2H), 5.00 (t, 3=7.3, 2H), 5.40-5.53 (m, 2H), 7.26 7.32 (2H), 7.41 (d, J=7.8, 1H), 7.64 (dd, J=1.3, 3.7 and 9.2, 1H), 7.68-7.73 (m, 1H). 132(D) 4,5-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-y1)but-3-ynyl)-2H benzord]1 ,2,3]triazole hydrochloride The title compound was prepared in accordance with the general method of Example 109(F), from 4,5-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-y)but-3-ynyl)-2H benzo[d][1,2,3]triazole (45 mg, 0.14 mmol) to yield the corresponding hydrochloride (50 mg, 0.14 mmol) as a white solid (M.P.: 157-159'C). LCMS (RT) : 4.41min; MS (ES+) gave m/z : 317.1. 1 H-NMR (DMSO[D] 6 ), 6 (ppm) : 3.32 (t, J=6.7, 2H), 5.04 (t, J=6.7, 2H), 5.32-5.45 (m, 2H), 5.40-5.70 (br. s, 1H), 7.31 (d, J=7.8, 1H), 7.42 (d, J=7.8, 1H), 7.55-7.61 (m, 1H), 7.80-7.85 (m, 1H), 7.89 (ddd, J=0.9, 3.8 and 9.3, 1H). Example 133 2-(4-(6-(Fluoromethv1)pridin-2-l)but-3-yny1)-2H-indazole The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (204 mg, 1.07 mmol) and 2-but-3 ynyl-2H-indazole (183 mg, 1.07 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 50 mg (0.18 mmol, 17%) of 2-(4 (6-(fluoromethyl)pyridin-2-yl)but-3-yny)-2H-indazole as a colorless oil. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.07 (t, J=7.3, 2H), 4.68 (t, J=7.3, 2H), 5.40-5.53 (m, 2H), 7.12 (d, J=7.7, 1H), 7.14-7.19 (m, 1H), 7.37-7.41 (2H), 7.52 (d, J=8.5, 1H), 7.64 7.69 (m, 1H), 7.75 (d, J=8.1, 1H), 8.04 (s, 1H). Example 134 2-(4-(6-(Difluoromethvl)pyridin-2-y)but-3-nv1)-2H-benzord]F1,2,31triazole 134(A) 2-Bromo-6-difluoromethyl-pyridine DAST (0.99 mL, 8.06 mmol) was added dropwise to a solution of 6-bromo-pyridine 2-carbaldehyde (1.00 g, 5.38 mmol) in DCM (28 mL) at 0 0 C. The reaction mixture was stirred for 24 hours at room temperature, quenched by the addition of saturated aqueous solution of NaHCO 3 and extracted twice with DCM. The organic phase was washed with water, dried over MgS04, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 0.74 g (3.56 mmol, 66%) of 2-bromo-6-difluoromethyl-pyridine as a yellow oil. 134(B) 2-(4-(6-(Difluorometh1)pyridin-2-vl)but-3-ynvl)-2H-benzo[d1l,2,3ltriazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(difluoromethyl)-pyridine (121 mg, 0.58 nmol) and 2-(but-3 ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 2 hours. The crude residue was purified by preparative chromatography plate (DCM/MeOH 99:1) to yield 15 mg (49 pLmol, 8%) of 2-(4-(6-(difluoromethyl)pyridin 2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a white solid (M.P.: 101.8-102.9'C). LCMS (RT) : 4.3 min; MS (ES+) gave m/z : 299.1. 'H-NMR CDCl 3 , 8 (ppm) : 3.32 (t, J=7.4, 2H), 5.01 (t, J=7.4, 2H), 6.49-6.71 (m, 1H), 7.38-7.45 (3H), 7.58 (d, J=7.7, 1H), 7.76-7.81 (m, 1H), 7.89 (dd, J=3.1 and 6.6, 2H).
WO 2005/123703 PCT/IB2005/002390 168 Example 135 4,6-Difluoro-2-(4-(pyridin-2-ylbut-3-ynyl)-2H-benzofdl[1,2,3ltriazol 135(A) 5,7-Difluoro-1H-benzofd1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3,5-difluorobenzene-1,2-diamine (520 mg, 3.61 mmol) to yield 5,7 difluoro-1H-benzo[d][1,2,3}triazole (492 mg, 3.17 inmol, 88%). 135(B) 2-(But-3-ynyl)-4,6-difluoro-2H-benzoFd1[1,2,3]triazole The title compound was prepared in accordance with the general method of Example 109(D), from 5,7-difluoro-1H-benzo[d][1,2,3]triazole (271 mg, 1.75 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 33%) of 2-(but-3-ynyl)-4,6-difluoro-2H-benzo[d][1,2,3]triazole. Rf (cyclohexane/AcOEt 9:1)= 0.3. 135(C) 4,6-Difluoro-2-(4-(pyridin-2-y)but-3-ynl)-2H-benzo[dl[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.26 mmol) and 2-(but-3-ynyl)-4,6-difluoro-2H benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 31 mg (0.11 mmol, 46%) of 4,6-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 99:1) = 0.1. LCMS (RT) : 4.03min; MS (ES+) gave m/z: 285.1. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.30 (t, J=7.4, 2H), 4.99 (t, J=7.4, 2H), 6.88-6.94 (m, 1H), 7.18-7.24 (m, 1H), 7.32 (dd, J=2.0 and 8.3, 1H), 7.35 (d, J=7.8, 1H), 7.60-7.65 (in, 1H), 8.55 (d, J=4.8, 1H). Example 136 4,5-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzodlr1,2,31triazole 136(A) 4,5-Difluoro-1H-benzo[d]Fl,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3,4-difluorobenzene-1,2-diamine (490 mg, 3.40 mmol) to yield 4,5 difluoro-1H-benzo[d][1,2,3]triazole (485 mg, 3.13 mmol, 92%). 136(B) 2-(But-3-yny1)-4,5-difluoro-2H-benzord 1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D) from 4,5-difluoro-1H-benzo[d][1,2,3]triazole (266 mg, 1.71 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 100 mg (0.48 mmol, 33%) of 2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole. Rf (DCM/MeOH 9:1) = 0.2. 136(C) 4,5 -Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl-2H-benzo dl[1,2,31 triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.26 mmol) and 2-(but-3-ynyl)-4,5-difluoro-2H benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 41 ing WO 2005/123703 PCT/IB2005/002390 169 (0.14 nmol, 60%) of 4,5-difluoro-2-(4-(pyridin-2-yl)but-3-yny)-2H benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 99:1) = 0.1. LCMS (RT) : 4.01min; MS (ES+) gave m/z: 285.2. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.31 (t, J=7.4, 2H), 5.00 (t, J=7.4, 2H), 7.20-7.24 (m, 1H), 7.26-7.32 (m, 1H), 7.35 (d, J=7.8, 1H), 7.60-7.66 (2H), 8.55 (d, J=4.8, 1H). Example 137 2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)-2H-benzofdll,2,3]triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methylpyridine (55 mg, 0.32 mmol) and 2-(but-3-ynyl)-2H benzo[d][1,2,3]triazole (50 mg, 0.29 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.15 mmol, 53%) of 2-(4-(6-methylpyridin-2-y)but-3-ynyl)-2H benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 98:2) = 0.2. LCMS (RT) : 3.23min; MS (ES+) gave m/z : 263.2. lH-NMR (CDC1 3 ), 8 (ppm) : 2.54 (s, 3H), 3.30 (t, J=7.6, 2H), 5.00 (t, J=7.6, 2H), 7.08 (d, J=7.7, 1H), 7.17 (d, J=7.7, 1H), 7.40 (dd, J=3.1 and 6.6, 2H), 7.48-7.53 (m, 1H), 7.88 (dd, J=3.1 and 6.6, 2H). Example 138 2-(4-(3-Fluoropyridin-2-vl)but-3-ynyl)-2H-benzod1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-chloro-3-fluoropyridine (42 mg, 0.32 mmol) and 2-(but-3-ynyl)-2H benzo[d][1,2,3]triazole (50 mg, 0.29 minol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 21 mg (80 [tmol, 27%) of 2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 98:2) = 0.1. LCMS (RT) : 3.91min; MS (ES+) gave m/z: 267.2. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.37 (t, J=7.6, 2H), 5.03 (t, J=7.6, 2H), 7.23-7.29 (2H), 7.38-7.43 (2H), 7.89 (dd, J=3.0 and 6.6, 2H), 8.35-8.40 (m, 1H). Example 139 5-Fluoro-2-(4-(6-(fluoromethvl)pyridin-2-yl)but-3-ynyl)-2H-benzord1l,2,31triazole 139(A) 5-Fluoro-1H-benzofd1l1,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 4-fluorobenzene-1,2-dianine (500 mg, 3.96 mnol) to yield 5-fluoro 1H-benzo [d] [1,2,3]triazole (376 mg, 2.74 mmol, 69%) as a dark solid. 139(B) 2-(But-3-ynyl)-5-fluoro-2H-benzod1l1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 5-fluoro-1H-benzo[d][1,2,3]triazole (360 mg, 2.63 mmol). The crude WO 2005/123703 PCT/IB2005/002390 170 residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 137 mg (0.72 mmol, 32%) of 2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole. Rf (cyclohexane/AcOEt 9:1) = 0.3. 139(C) 5-Fluoro-2-(46-(fluoromethllpyridin-2-yl)but-3-vnvl)-2H benzofd1[1,2,3]triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (55 mg, 0.29 mmol) and 2-(but-3-ynyl)-5 fluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.26 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 50 mg (0.17 mmol, 64%) of 5-fluoro-2-(4-(6-fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 99:1)= 0.1. LCMS (RT) : 4.26min; MS (ES+) gave m/z : 299.2. 1 H-NMR (CDC1 3 ), 5 (ppm) : 3.29 (t, J=7.4, 2H), 4.97 (t, J=7.4, 2H), 5.40-5.53 (m, 2H), 7.18-7.24 (in, 1H), 7.28 (d, J=7.8, 1H), 7.41 (d, J=7.8, 1H), 7.47 (ddd, J=0.5, 2.3 and 8.7, 1H), 7.68-7.72 (m, 1H), 7.86 (ddd, J=0.5, 4.8 and 9.2, 1H). Example 140 2-(4-(4-(4-Fluoropheny)-1H-pyrazol-1-vl)but-l-ynyl)pyridine 140(A) 1-But-3-ynyl-4-(4-fluoro-phenyl)-1H-prazole The title compound was prepared in accordance with the general method of Example 109(D), from 4-(4-fluoro-phenyl)-1H-pyrazole (255 ing, 1.57 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 223 mg (1.04 mmol, 73%) of 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole. 140(B) 2-(4-(4-(4-Fluorophenvl)-1H-pyrazol-1 -v)but-1-vnv1)pyridine The title compound was prepared in accordance with the general method of Example 1, from 50 mg (0.23 mmol) of 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole. Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) and SCX column (DCM, DCM/MeOH 95:5, DCM/MveOH/NIOH 94:5:1) to yield 2 mg (7 pmol, 3%) of 2-(4-(4-(4 fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid. LCMS (RT) : 3.88min; MS (ES+) gave m/z : 292.2. Rf (DCM/MeOH 98:2) = 0.3. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.05 (t, J=6.9, 2H), 4.42 (t, J=6.9, 2H), 7.03-7.27 (2H), 7.19-7.24 (in, 1H), 7.34 (d, J=7.8, 1H), 7.41-7.45 (2H), 7.58-7.64 (m, 1H), 7.76 (d, J=8.3, 2H), 8.55-8.59 (in, 1H). Example 141 2-(4-(2-Methylthiazol-4-y)but-3-vnvl)-2H-benzo[d[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 4-bromo-2-methylthiazole (30 mg, 0.13 mmol) and 2-(but-3-ynyl)-2H benzo[d][1,2,3]triazole (30 mg, 0.17 mmol, Example 109(D)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) WO 2005/123703 PCT/IB2005/002390 171 to yield 18 mg (66 pimol, 50%) of 2-(4-(2-methylthiazol-4-yl)but-3-yny)-2H benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 98:2) = 0.2. LCMS (RT) : 4.01min; MS (ES+) gave m/z: 269.1. 'H-NMR (CDC1 3 ), 6 (ppm) : 2.69 (s, 3H), 3.27 (t, J=7.6, 2H), 4.97 (t, J=7.6, 2H), 7.20 (s, 1H), 7.40 (dd, J=3.1 and 6.6, 2H), 7.88 (dd, J=3.1 and 6.6, 2H). Example 142 2-(4-(4-o-Tolvl-1H-pyrazol-1-vl)but-1 -ynvl)pyridine 142(A) 1-But-3-ynyl-4-o-tolyl- 1H-pyrazole The title compound was prepared in accordance with the general method of Example 109(D), from 4-o-tolyl-1H-pyrazole (325 mg, 2.05 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 318 mg (1.51 mmol, 88%) of 1-but-3-ynyl-4-o-tolyl-1H-pyrazole. 142(B) 2-(4-(4-o-Tolvl-1H-pyrazol-1-vl)but-1-ynyl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 50 mg (0.24 mmol) of 1-but-3-ynyl-4-o-tolyl-1H-pyrazole. Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) and SCX column (DCM, DCM/MeOH 95:5, DCM/MeOH/NH 4 0H 94:5:1) to yield 2 mg (9 ptmol, 4%) of 2-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as an orange oil. LCMS (RT) : 4.03min; MS (ES+) gave m/z: 288.2. Rf (DCM/MeOH 98:2) = 0.2. 1 H-NMR (CDC1 3 ), 5 (ppm) : 2.37 (s, 3H), 3.07 (t, J=6.9, 2H), 4.45 (t, J=6.9, 2H), 7.17-7.25 (4H), 7.32-7.36 (2H), 7.59-7.64 (m, 1H), 7.65 (s, 1H), 7.68 (s, 1H), 8.54 8.58 (m, 1H). Example 143 2-(Fluoromethyl)-6-(4-(4-o-tolvl-1H-pyrazol-1-V)but- 1 -vnv)pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.26 mmol) and 1-but-3-ynyl-4-o tolyl-1H-pyrazole (50 mg, 0.24 mmol, Example 142(A)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 23 mg (72 ptmol, 30%) of 2-(fluoromethyl)-6-(4-(4-o-tolyl-1H-pyrazol-1-yl)but-1 ynyl)pyridine as a yellow solid with a purity of 81%. Rf (DCM/MeOH 98:2) 0.2. LCMS (RT) : 4.43min; MS (ES+) gave m/z : 320.2. 'H-NMR (CDC1 3 ), 8 (ppm) : 2.37 (s, 3H), 3.07 (t, J=6.9, 2H), 4.44 (t, J=6.9, 2H), 5.40-5.53 (m, 2H), 7.17-7.25 (3H), 7.27-7.32 (m, 1H), 7.32-7.43 (2H), 7.65 (s, 1H), 7.68 (s, 1H), 7.68-7.72 (m, 1H).
WO 2005/123703 PCT/IB2005/002390 172 Example 144 2-(Fluoromethvl)-6-(4-(4-(4-fluorophenv1)-1H-pyrazol-1-v1)but- 1-Ynyl)vridine The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (49 mg, 0.26 mmol) and 1-but-3-ynyl-4 (4-fluoro-phenyl)-1H-pyrazole (50 mg, 0.23 mmol, Example 140(A)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 29 mg (88 pimol, 38%) of 2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl) 1H-pyrazol- 1 -yl)but- 1 -ynyl)pyridine as a yellow solid. Rf (DCM/MeOH 98:2)= 0.2. LCMS (RT) : 4.29min; MS (ES+) gave m/z : 324.2. 1 H-NMR (CDC1 3 ), 5 (ppm) : 3.05 (t, J=6.9, 2H), 4.42 (t, J=6.9, 2H), 5.40-5.53 (m, 2H), 7.03-7.18 (2H), 7.27-7.32 (m, 1H), 7.38-7.45 (3H), 7.66-7.71 (m, 1H), 7.73 (s, 1H), 7.77 (s, 1H). Example 145 6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-v1)but-3-vnv1)quinoxaline 145(A) 6-Fluoro-2-methyl-quinoxaline A solution of 2-oxo-propionaldehyde (0.19 mL, 1.20 mmol) and 4-fluoro-benzene 1,2-diamine (150 mg, 1.19 mmol) in water (1.3 mL) was placed in a microwave tube and heated for 1 min. at 150W. Then the reaction mixture was diluted with water and extracted twice with AcOEt. The organic phase was washed with water, brine, dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 154 mg (0.95 mmol, 80%) of 6 fluoro-2-methyl-quinoxaline. LCMS (RT) : 3.24min; MS (ES+) gave m/z : 163.2. 145(B) 6-Fluoro-2-(4-trimethylsilanyl-but-3-vnyl)-guinoxaline The title compound was prepared in accordance with the general method of Example 118(A), from 6-fluoro-2-methyl-quinoxaline (100 mg, 0.62 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 66 mg (0.24 mmol, 39%) of 6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orange oil. LCMS (RT) : 5.34min; MS (ES+) gave m/z: 273.3. 145(C) 2-But-3-vnvl-6-fluoro-quinoxaline The title compound was prepared in accordance with the general method of Example 108(B), from 6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (298 mg, 1.09 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 94:6 to 90:10) to yield 90 mg (0.45 mmol, 41%) of 2-but-3-ynyl-6-fluoro-quinoxaline as a yellow liquid. LCMS (RT) : 3.89min; MS (ES+) gave m/z : 201.2.. 145(D) 6-Fluoro-2-(4-(6-(fluoromethvl)pyridin-2-vl)but-3-ynv1)quinoxaline The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (43 mg, 0.22 mmol) and 2-but-3 ynyl-6-fluoro-quinoxaline (45 mg, 0.22 mmol). Microwave conditions: 120'C for 15 WO 2005/123703 PCT/IB2005/002390 173 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 45 mg (0.15 mmol, 65%) of 6-fluoro-2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as an orange solid with a purity of 85%. LCMS (RT) : 4.21min; MS (ES+) gave m/z: 310.3. 1 H-NMR (CDCl 3 ), 8 (ppm) : 3.05 (t, J=7.3, 2H), 3.36 (t, J=7.3, 2H), 5.40-5.53 (m, 2H), 7.26-7.30 (m, 1H), 7.39 (d, J=7.8, 1H), 7.49-7.55 (m, 1H), 7.65-7.71 (2H), 8.10 (dd, J=5.8 and 9.2, 1H), 8.82 (s, 1H). Example 146 4-Chloro-2-(4-(pyridin-2-yllbut-3-ynyl)-2H-benzofd1l,2,31triazole 146(A) 4-Chloro-lH-benzo[dl[l,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3-chlorobenzene-1,2-diamine (1.00 g, 7.01 mmol) to yield 4-chloro-1H benzo[d][1,2,3]triazole (975 mg, 6.35 mmol, 91%) as a dark solid. 146(B) 2-(But-3-ynyl)-4-chloro-2H-benzordl,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 4-chloro-1H-benzo[d][1,2,3]triazole (504 mg, 3.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 93:7) to yield 60 mg (0.29 mmol, 10%) of 2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 97:3)= 0.3. 146(C) 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzod]11,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (25 mg, 0.16 mmol) and 2-(but-3-ynyl)-4-chloro-2H benzo[d][1,2,3]triazole (30 mg, 0.15 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 12 mg (42 ptmol, 29%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange solid. Rf (DCM/MeOH 99:1)= 0.05. LCMS (RT) : 3.96min; MS (ES+) gave m/z: 283.1. 'H-NMR (CDCl 3 ), 6 (ppm) : 3.32 (t, J=7.5, 2H), 5.03 (t, J=7.5, 211), 7.21 (ddd, J=1.1, 4.9 and 7.6, 111), 7.31-7.38 (211), 7.41 (d, J=7.3, 111), 7.59-7.65 (m, 1H), 7.80 (dd, J=0.5 and 8.5, 1H), 8.55 (dd, J=0.5 and 4.9, 1H). Example 147 4-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynvl)-2H-benzordl1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (30 mg, 0.16 mmol) and 2-(but-3-ynyl)-4 chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol, Example 146(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 16 mg (51 tmol, 35%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2 yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown oil. Rf (DCM/MeOH 99:1) = 0.1.
WO 2005/123703 PCT/IB2005/002390 174 LCMS (RT) : 4.44min; MS (ES+) gave m/z : 315.1, 317.2. 'H-NMR (CDCl 3 ), 5 (ppm) : 3.32 (t, J=7.4, 2H), 5.03 (t, J=7.4, 2H), 5.40-5.53 (m, 2H), 7.27-7.35 (2H), 7.40-7.43 (2H), 7.69-7.72 (m, 1H), 7.80 (d, J=8.5, 1H). Example 148 6,7-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-v1)but-3-ynv1)quinoxaline 148(A) 6,7-Difluoro-2-methyl-quinoxaline The title compound was prepared in accordance with the general method of Example 145(A), from 4,5-difluoro-benzene-1,2-diamine (400 mg, 2.77 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 333 mg (1.85 mmol, 67%) of 6,7-difluoro-2-methyl-quinoxaline. LCMS (RT) : 3.56min; MS (ES+) gave m/z : 181.1. 148(B) 6,7-Difluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline The title compound was prepared in accordance with the general method of Example 118(A), from 6,7-difluoro-2-methyl-quinoxaline (333 mg, 1.85 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 233 mg (0.85 mmol, 46%) of 6,7-difluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orange oil. LCMS (RT) : 5.59min; MS (ES+) gave m/z : 291.3. 148(C) 2-But-3-ynyl-6,7-difluoro-quinoxaline The title compound was prepared in accordance with the general method of Example 108(B), from 6,7-difluoro-2-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (233 mg, 0.85 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 80 mg (0.37 mmol, 52%) of 2-but-3-ynyl-6,7 difluoro-quinoxaline as an orange solid. LCMS (RT) : 4.19min; MS (ES+) gave m/z : 219.1. 148(D) 6,7-Difluoro-2-(4-(6-(fluoromethvl)pyridin-2-yl)but-3-ynvl)quinoxaline The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (70 mg, 0.37 mmol) and 2-but-3 ynyl-6,7-difluoro-quinoxaline (80 mg, 0.37 mmol). Microwave conditions: 120'C for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 16 mg (50 pmol, 14%) of 6,7-difluoro-2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as a yellow solid (M.P.: 134.9 138.5-C). LCMS (RT) : 4.44min; MS (ES+) gave m/z: 328.1. 1 H-NMR (CDCl 3 ), S (ppm) : 3.04 (t, J=7.3 2H), 3.35 (t,. J=7.3, 2H), 5.40-5.53 (m, 2H), 7.25-7.29 (m, 1H), 7.39 (d, J=7.8, 1H), 7.67-7.72 (m, 1H), 7.78-7.88 (2H), 8.82 (s, 1H). Example 149 4-Fluoro-2-(4-(6-(fluoromethvl)pyridin-2-vl)but-3-ynvl)-2H-indazole WO 2005/123703 PCT/IB2005/002390 175 149(A) 4-Fluoro-2-(4-trimethylsilanyl-but-3-yny1)-2H-indazole 2-Fluoro-6-nitro-benzaldehyde (180 mg, 1.06 mmol) was added to a solution of 4 trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol) in toluene (2 mL) and the reaction mixture was stirred under reflux for 30 min in a Dean-Stark. After evaporation of the solvent, the crude product was dissolved in triethylphosphite (1 mL) and the reaction mixture was stirred at 80'C for 4 hours. After evaporation, the crude product was purified by by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 4-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (142 mg, 0.59 mmol, 52%) as a yellow oil. Rf (cyclohexane/AcOEt 4:1)= 0.3. LCMS (RT) : 5.01min; MS (ES+) gave m/z : 261.1. 149(B) 2-But-3-vnvl-4-fluoro-2H-indazole The title compound was prepared in accordance with the general method of Example 108(B), from 4-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (142 mg, 0.59 mmol) to yield 104 mng (0.55 mmol) of 2-but-3-ynyl-4-fluoro-2H-indazole. 149(C) 4-Fluoro-2-(4-(6-(fluoromethl)pyridin-2-vl)but-3-vnv1)-2H-indazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (0.12 g, 0.61 mmol) and 2-but-3-ynyl-4 fluoro-2H-indazole (104 mg, 0.55 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 60 mg (0.20 mmol, 36%) of 4-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid. Rf (cyclohexane/AcOEt 1:1)= 0.2. LCMS (RT) : 4.04min; MS (ES+) gave m/z : 298.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.18 (t, J=6.9, 2H), 4.68 (t, J=6.9, 2H), 5.41-5.54 (m, 2H), 6.71 (dd, J=7.5 and 10.4, 1H), 7.19-7.25 (m, 1H), 7.26-7.29 (m, 1H), 7.42 (d, J=7.9, 1H), 7.50 (d, J=8.7, 1H), 7.68-7.73 (m, 1H), 8.14 (s, 1H). Example 150 4-Chloro-2-(4-(pridin-2-yl)but-3-vnvl)-2H-indazole 150(A) 4-Chloro-2-(4-trimethylsilanyl-but-3-vnv1)-2H-indazole The title compound was prepared in accordance with the general method of Example 149(A), from 2-chloro-6-nitro-benzaldehyde (210 mg, 1.13 nmol) and 4 trimethylsilanyl-but-3-ynylamine (210 mg, 1.50 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 4-chloro-2 (4-trimethylsilanyl-but-3-ynyl)-2H-indazole (134 mg, 0.48 mmol, 43%) as a yellow oil. Rf (cyclohexane/AcOEt 4:1)= 0.3. LCMS (RT) : 5.2lmin; MS (ES+) gave m/z : 277.1. 150(B) 2-But-3-vnv1-4-chloro-2H-indazole The title compound was prepared in accordance with the general method of Example 108(B), from 4-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (134 mg, 0.48 mmol) to yield 99 mg (0.48 mmol) of 2-but-3-ynyl-4-chloro-2H-indazole. 150(C) 4-Chloro-2-(4-(pyridin-2-vl)but-3-vnv)-2H-indazole WO 2005/123703 PCT/IB2005/002390 176 The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.27 mmol) and 2-but-3-ynyl-4-chloro-2H-indazole (50 mg, 0.24 mnol). Reaction time: 8 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 12 mg (43 tmol, 17%) of 4 chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid. Rf (cyclohexane/AcOEt 1:1) = 0.1. LCMS (RT): 3.91min; MS (ES+) gave mz: 282.1. H-NMR (CDC1 3 ), (ppm) : 3.18 (t, J=6.9, 2H), 4.69 (t, J=6.9, 2H), 7.08 (d, J=7.1, 111), 7.20-7.25 (2H), 7.33 (d, J=7.8, 1H), 7.60-7.65 (2H), 8.16 (s, 1H), 8.57 (d, J=4.3, 1H). Example 151 6-Fluoro-2-(4-(6-(fluoromethvl)pyridin-2-v1)but-3-vnv1)-2H-indazole 151(A) 6-Fluoro-2-(4-trimethylsilanvl-but-3-vnl)-2H-indazole The title compound was prepared in accordance with the general method of Example 149(A), from 4-fluoro-2-nitro-benzaldehyde (180 mg, 1.06 mmol) and 4 trimethylsilanyl-but-3-ynylamine (200 mg, 1.40 mmol). The crude product was purified by by flash chromatography (cyclohexane/AcOEt 4:1) to yield 6-fluoro-2-(4 trimethylsilanyl-but-3-ynyl)-2H-indazole (310 mg, 1.06 mmol). 151(B) 2-But-3-vnyl-6-fluoro-2H-indazole The title compound was prepared in accordance with the general method of Example 108(B), from 6-fluoro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole (310 mg, 1.13 mmol) to yield 93 mg (0.49 nmol, 43%) of 2-but-3-ynyl-6-fluoro-2H-indazole as an orange oil. 151(C) 6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynvl)-2H-indazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (100 mg, 0.54 nmol) and 2-but-3-ynyl-6 fluoro-2H-indazole (93 mg, 0.49 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 40 mg (0.13 mmol, 27%) of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid. Rf (cyclohexane/AcOEt 1:1) = 0.2. LCMS (RT) : 3.93min; MS (ES+) gave m/z : 298.1. 'H-NMR (CDCl 3 ), 6 (ppm) : 3.17 (t, J=6.9, 211), 4.65 (t, J=6.9, 211), 5.40-5.53 (m, 2H), 6.88-6.93 (m, 1H), 7.26 (d, J=7.8, 1H), 7.28-7.32 (m, 1H), 7.41 (d, J=7.8, 1H), 7.60-7.65 (in, 1H), 7.67-7.72 (m, 1H), 8.05 (s, 1H). Example 152 4-Chloro-2-(4-(6-(fluoromethyllpyridin-2-v1)but-3-vnl)-2H-indazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (51 mg, 0:27 mmol) and 2-but-3-ynyl-4 chloro-2H-indazole (50 mg, 0.24 mmol, Example 150(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to WO 2005/123703 PCT/IB2005/002390 177 yield 54 mg (0.17 mmol, 70%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 ynyl)-2H-indazole as a brown solid. Rf (cyclohexane/AcOEt 1:1) = 0.2. LCMS (RT) : 4.29min; MS (ES+) gave m/z : 314.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.18 (t, J=6.9, 2H), 4.69 (t, J=6.9, 2H), 5.41-5.54 (in, 2H), 7.08 (d, J=7.2, 1H), 7.20-7.24 (m, 1H), 7.26-7.30 (m, 1H), 7.42 (d, J=7.8, 1H), 7.62 (d, J=8.7, 1H), 7.68-7.72 (m, 1H), 8.15 (s, 1H). Example 153 5,6-Difluoro-2-(4-(pyridin-2-vl)but-3-ynyl)-2H-benzofdl[1,2,31triazole 153(A) 5,6-Difluoro-1H-benzo d11,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 4,5-difluorobenzene-1,2-diamine (420 mg, 2.91 mmol) to yield 5,6 difluoro-1H-benzo[d][1,2,3]triazole (361 mg, 2.33 mmol, 80%) as a dark solid. 153(B) 2-(But-3-yny1)-5,6-difluoro-2H-benzordl[1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 5,6-difluoro-lH-benzo[d][1,2,3]triazole (389 mg, 2.51 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 244 mg (1.18 mmol, 52%) of 2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole as a white solid. Rf (cyelohexane/AcOEt 4:1) = 0.4. 153(C) 5,6-Difluoro-2-(4-(pyridin-2-vl)but-3-ynyll-2H-benzo[d11,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (50 mg, 0.32 mmol) and 2-(but-3-ynyl)-5,6-difluoro-2H benzo[d][1,2,3]triazole (60 mg, 0.29 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 54 mg (0.19 mol, 66%) of 5,6-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as a yellow solid (M.P. = 131-132'C). Rf (DCM/MeOH 99:1) = 0.1. LCMS (RT) : 3.85min; MS (ES+) gave m/z : 285.1. 1 H-NMR (CDC1 3 ), 6 (ppm) : 3.28 (t, J=7.4, 2H), 4.95 (t, J=7.4, 2H), 7.20-7.23 (m, IH), 7.33 (d, J=7.8, 1H), 7.58-7.64 (3H), 8.55 (d, J=4.3, 1H). Example 154 5.,6-Difluoro-2-(4-(6-(fluoromethyl)pridin-2-yl)but-3-nyll-2H benzordl[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.32 nunol) and 2-(but-3-ynyl) 5,6-difluoro-2H-benzo[d][1,2,3]triazole (60 mg, 0.29 nmol, Example 153(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 29 mg (92 Lmol, 32%) of 5,6-difluoro-2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid (M.P. = 104-105-C). Rf (DCM/MeOH 99:1) = 0.1.
WO 2005/123703 PCT/IB2005/002390 178 LCMS (RT) : 4.28min; MS (ES+) gave m/z: 317.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.28 (t, J=7.4, 2H), 4.95 (t, J=7.4, 2H), 5.40-5.53 (m, 2H), 7.29 (d, J=7.8, 1H), 7.41 (d, J=7.8, 1H), 7.57-7.63 (2H), 7.68-7.73 (m, 1H). Example 155 7-Fluoro-2-(4-(6-(fluoromethv1)pyridin-2-v1)but-3-vnv1)-2H-indazole 155(A) 7-Fluoro-2-(4-trimethylsilanyl-but-3-vnyl)-2H-indazole The title compound was prepared in accordance with the general method of Example 149(A), from 3-fluoro-2-nitro-benzaldehyde (0.2 g, 1.2 mmol) and 4-trimethylsilanyl but-3-ynylamine (0.22 g, 1.5 nmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 92.5:7.5) to yield 7-fluoro-2-(4 trimethylsilanyl-but-3-ynyl)-2H-indazole (117 mg, 0.45 mmol) as a yellow oil. Rf (cyclohexane/AcOEt 4:1)= 0.1. LCMS (RT) : 4.83min; MS (ES+) gave m/z : 261.1. 155(B) 2-But-3-ynyl-7-fluoro-2H-indazole The title compound was prepared in accordance with the general method of Example 108(B), from 7-fluoro-2-(4-trimethylsilanyl-but-3-yny)-2H-indazole (134 mg, 0.48 mmol) to yield 99 mg (0.48 mmol) of 2-but-3-ynyl-7-fluoro-2H-indazole. 155(C) 7-Fluoro-2-(4-(6-(fluoromethv1)pyridin-2-vl)but-3-vnvl)-2H-indazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-fluoromethylpyridine (93 mg, 0.49 mmol) and 2-but-3-ynyl-7 fluoro-2H-indazole (84 mg, 0.45 mmaol). Reaction time: 6 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 17 mg (57 mol, 13%) of 7-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid. Rf (cyclohexane/AcOEt 1:1) = 0.2. LCMS (RT) : 3.83min; MS (ES+) gave mz : 298.1. IH-NMR (CDC1 3 ), S (ppm) : 3.17 (t, J=6.9, 2H), 4.66 (t, J=6.9, 2H), 5.40-5.54 (m, 2H), 7.07-7.13 (m, 1H), 7.23 (dd, J=1.9 and 9.1, 1H), 7.26 (d, J=7.8, 1H), 7.41 (d, J=7.8, 1H), 7.67-7.71 (2H), 8.01 (s, 1H). Example 156 4-Chloro-2-(4-(1-methyl-lH-pyrazol-3-yl)but-3-vnvl)-2H-benzordlr1,2,3]triazole The title compound was prepared in accordance with the general method of Example 108(C), from 3-bromo-1-methyl-1H-pyrazole (70 mg, 0.43 mmol) and 2-but-3-ynyl 4-chloro-2H-benzo[d][1,2,3]triazole (89 mg, 0.43 mmol, Example 146(B)). Microwave conditions: . The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 12 mg (42 imol, 10%) of 4-chloro-2-(4-(l-methyl 1H-pyrazol-3-yl)but-3-ynyl)-21-benzo[d][1,2,3]triazole as a brown semi-solid. Rf (cyclohexane/AcOEt 7:3) = 0.2. LCMS (RT) : 3.93min; MS (ES+) gavem/z : 286.1, 288.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.27 (t, J=7.6, 2H), 3.88 (s, 3H), 5.00 (t, J=7.6, 2H), 6.31 (d, J=2.2, 1H), 7.28 (d, J=2.2, 1H), 7.32 (dd, J=7.4 and 8.5,1H), 7.41 (dd, J=0.7 and 7.4, 1H), 7.79 (dd, J=0.7 and 8.5, 1H).
WO 2005/123703 PCT/IB2005/002390 179 Example 157 6-(4-(4,6-Difluoro-2H-benzo[d1l,2,3]triazol-2-v1)but-1-ynl)pyridin-2-anine The title compound was prepared in accordance with the general method of Example 1, from 6-bromo-pyridin-2-ylamine (60 mg, 0.35 mmol) and 2-but-3-ynyl-4,6 difluoro-2H-benzo[d][1,2,3]triazole (72 mg, 0.35 mmol, Example 135(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 65 mg (0.22 mmol, 63%) of 6-(4-(4,6-difluoro-2H benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-amine as a brown solid. Rf (DCM/AcOEt 1:1) = 0.2. LCMS (RT): 2.63min; MS (ES+) gave m/z: 300.1. 'H-NMR (CDC1 3 ), S (ppm) : 3.27 (t, J=7.5, 2H), 4.45-4.53 (br. s, 2H), 4.97 (t, J=7.5, 2H), 6.45 (d, J=8.3, 1H), 6.75 (d, J=7.3, 1H), 6.88-6.95 (m,1H), 7.31 (dd, J=2.0 and 8.3, 1H), 7.37 (dd, J=7.3 and 8.3, 1H). Example 158 2-(4-(2H-Benzo[dl1,2,31triazol-2-yl)but-1--ynyl)-6-methylpyridin-3-amine The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methyl-pyridin-3-ylamine (80 mg, 0.43 mmol) and 2-but-3-ynyl 2H-benzo[d][1,2,3]triazole (73 mg, 0.43 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 53 mg (0.19 mmol, 45%) of 2-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-6 methylpyridin-3-amine as a brown solid. Rf (DCM/AcOEt 1:1) = 0.2. LCMS (RT) : 2.33min; MS (ES+) gave m/z : 278.1. 'H-NMR (CDC1 3 ), S (ppm) : 2.40 (s, 3H), 3.31 (t, J=6.7, 2H), 4.10-4.18 (br. s, 2H), 5.02 (t, J=6.7, 2H), 6.87-6.91 (2H), 7.41 (dd, J=3.1 and 6.6, 2H), 7.87 (dd, J= 3.1 and 6.6, 2H). Example 159 2-(4-(3-Phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine 159(A) 1-But-3-ynyl-3 -phenyl-lH-pyrazole The title compound was prepared in accordance with the general method of Example 109(D), from 3-phenyl-lH-pyrazole (617 mg, 4.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 140 mg (0.71 mmol, 25%) of 1-but-3-ynyl-3-phenyl-l1H-pyrazole. 159(B) 2-(4-(3-Phenvl-1H-pyrazol-1-yl)but-1-ynyl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 140 mg (0.71 mmol) of 1-but-3-ynyl-3-phenyl-lH-pyrazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 44 mg (0.16 mmol, 22%) of 2-(4-(3 -phenyl- 1H-pyrazol-1 -yl)but- 1 -ynyl)pyridine as a yellow solid. LCMS (RT) : 3.84min; MS (ES+) gave m/z: 274.1. Rf (DCM/MeOH 97:3) = 0.2.
WO 2005/123703 PCT/IB2005/002390 180 Example 160 4-Nitro-2-(4-(pyridin-2-vl)but-3-yny1)-2H-benzofdll,2,31triazole 160(A) 4-Nitro-lH-benzodl[1,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3-nitro-benzene-1,2-diamine (2.50 g, 16.3 mmol) to yield 4-nitro-lH benzo[d][1,2,3]triazole (2.65 g, 16.1 nmmol) as a dark solid. 160(B) 2-But-3-vnyl-4-nitro-2H-benzodl[1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 4-nitro-1H-benzo[d][1,2,3]triazole (1.35 g, 8.20 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5 to 90:10) to yield 191 mg (0.88 mmol, 12%) of 2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole. Rf (cyclohexane/AcOEt 9:1)= 0.1. 160(C) 4-Nitro-2-(4-(pyridin-2-y1)but-3-yny1)-2H-benzod]l1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (76 mg, 0.48 mmol) and 2-but-3-ynyl-4-nitro-2H benzo[d][1,2,3]triazole (95 mg, 0.44 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 31%) of 4-nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as an orange oil. Rf (DCM/MeOH 99:1)= 0.1. LCMS (RT) : 3.47min; MS (ES+) gave m/z : 294.1. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.12 (t,J=6.9, 2H), 5.37 (t, J=6.9, 2H), 7.18-7.22 (m, 1H), 7.26-7.30 (m, 1H), 7.50-7.54 (m, 1H), 7.59-7.64 (m, 1H), 8.38 (dd, J=0.9 and 7.8, 1H), 8.45 (dd, J=0.9 and 8.2, iH), 8.49-8.53 (m, iH). Example 161 2-(4-(6-(Fluoromethv1)pvridin-2-yl)but-3-yny1)-4-nitro-2H-benzo[dl[1.2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (92 mg, 0.48 mmol) and 2-but-3-ynyl-4 nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol, Example, 160(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 59 mg (0.18 mol, 42%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 ynyl)-4-nitro-2H-benzo[d][1,2,3]triazole as an orange oil. Rf (DCM/MeOH 99:1) = 0.1. LCMS (RT) : 3.97min; MS (ES+) gave m/z: 326.1. 'H-NMR (CDC1 3 ), 8 (ppm) : 3.12 (t, J=6.8, 2H), 5.37 (t, J=6.8, 2H), 5.36 (m, 2H), 7.24 (d, J=7.7, 1H), 7.39 (d, J=7.7, iH), 7.50-7.56 (m, iH), 7.67-7.72 (m, iH), 8.38 (dd, J=0.9 and 7.8, 1H), 8.46 (dd, J=0.9 and 8.2, 1H).
WO 2005/123703 PCT/IB2005/002390 181 Example 162 2-(4-(Pyridin-2-yl)but-3-vnvl)-2H-benzofdl[1,2,31triazol-4-anne The title compound was prepared in accordance with the general method of Example 62(A), from 4-nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole (40 mg, 0.14 mmol, Example 160(C)). The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 7 mg (27 ptmol, 19%) of 2-(4-(pyridin 2-yl)but-3-yny)-2H-benzo[d][1,2,3]triazol-4-amine as an orange solid. Rf (DCM/MeOH 98:2) = 0.03. LCMS (RT) : 2.62min; MS (ES+) gave m/z : 264.1. 'H-NMR (CDC1 3 ), 6 (ppm) : 3.22 (t, J=6.7, 2H), 4.00-4.30 (br. s, 2H), 5.12 (t, J=6.7, 2H), 6.72 (dd, J=0.5 and 7.3, 1H), 7.12-7.18 (2H), 7.20-7.24 (m, 1H), 7.56 (d, J=8.4, 1H), 7.57-7.62 (m, 1H), 8.55 (d, J=4.3, 1H). Example 163 4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzofdl[1,2,31triazole 163(A) 4-Methyl-1H-benzo[d1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3-methyl-benzene-1,2-diamine (1.95 g, 16.0 mmol) to yield 4-methyl 1H-benzo[d][1,2,3]triazole (1.76 g, 13.2 mmol, 83%) as a dark solid. 163(B) 2-But-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole The title compound was prepared in accordance with the general method of Example 109(D), from 4-methyl-lH-benzo[d][1,2,3]triazole (418 mg, 3.14 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 255 mg (1.38 mmol, 48%) of 2-but-3-ynyl-4-methyl-2H-benzo[d] [1,2,3 ]triazole. Rf (cyclohexane/AcOEt 9:1) = 0.2. 163(C) 4-Methyl-2-(4-(pvridin-2-yl)but-3-ynyl)-2H-benzo[dl[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (66 mg, 0.42 nimol) and 2-but-3-ynyl-4-methyl-2H benzo[d][1,2,3]triazole (70 mg, 0.38 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOIH 99:1) to yield 50 ing (0.19 mmol, 50%) of 4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as a yellow semi-solid. Rf (DCM/MeOH 98:2) = 0.1. LCMS (RT) : 3.73min; MS (ES+) gave m/z : 263.1. 'H-NMR (CDCl 3 ), 6 (ppm) : 2.67 (s, 3H), 3.30 (t, J=7.5, 2H), 5.00 (t, J=7.5, 2H), 7.12-7.16 (in, 1H), 7.21 (ddd, J=1.1, 4.9 and 7.6, 1H), 7.27-7.31 (in, 1H), 7.33-7.36 (in, 1H), 7.59-7.64 (m, 1H), 7.69 (d, J=8.6, 1H), 8.55 (d, J=4.3, 1H). Example 164 2-(4-(6-(Fluoromiethvl)pyridin-2-Yl)but-3-nyl)-4-meth1-2H-benzold1[l ,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and 2-but-3-ynyl-4- WO 2005/123703 PCT/IB2005/002390 182 methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol, 163(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 65 mg (0.22 mmol, 63%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl) 4-methyl-2H-benzo[d][1,2,3]triazole as a yellow semi-solid. Rf (DCM/MeOH 98:2) = 0.7. LCMS (RT): 4.22min; MS (ES+) gave m/z: 295.1. 'H-NMR (CDC1 3 ), 6 (ppm) : 2.67 (s, 3H), 3.30 (t, J=7.5, 2H), 5.00 (t, J=7.5, 2H), 5.40-5.53 (m, 2H), 7.12-7.16 (m, 1H), 7.27-7.31 (2H), 7.41 (d, J=7.8, 1H), 7.67-7.72 (2H). Example 165 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzoldi11,2,31triazole 165(A) 5-Methyl-1H-benzord][1,2,3ltriazole The title compound was prepared in accordance with the general method of Example 127(A), from 4-methyl-benzene-1,2-diamine (2.02 g, 16.5 mmol) to yield 5-methyl 1H-benzo[d][1,2,3]triazole (2.05 g, 15.4 mmol, 93%). 165(B) 2-But-3-ynyl-5-methyl-2H-benzord][1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 5-methyl-1H-benzo[d][1,2,3]triazole (418 mg, 3.14 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 135 mg (0.73 mmol, 26%) of 2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole. Rf (cyclohexane/AcOEt 9:1) = 0.3. 165(C) 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H benzord] F1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and 2-but-3-ynyl-5 methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 39%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl 2H-benzo[d][1,2,3]triazole as a yellow solid. Rf (DCM/MeOH 99:1)= 0.1. LCMS (RT) : 4.20min; MS (ES+) gave m/z: 295.1. 1 H-NMR (CDC1 3 ), 6 (ppm) : 2.50 (s, 3H), 3.28 (t, J=7.5, 2H), 4.96 (t, J=7.5, 2H), 5.40-5.53 (m, 211), 7.23 (dd, J=1.4 and 8.8, 1H), 7.29 (d, J=7.7, 1H), 7.40 (d, J=7.8, 1H), 7.60-7.62 (m, 1H), 7.67-7.72 (m, 1H), 7.76 (d, J=8.8, 1H). Example 166 5-Methv1-2-(4-(pyridin-2-vl)but-3-ynvl)-2H-benzo[d1l,2,31triaz6le The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (66 mg, 0.42 mmol) and 2-but-3-ynyl-5-methyl-2H benzo[d][1,2,3]triazole (70 mg, 0.38 mmol, Example 165(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 36 mg (0.14 mmol, 37%) of 5-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as an orange solid.
WO 2005/123703 PCT/IB2005/002390 183 Rf (DCM/MeOH 99:1) = 0.05. LCMS (RT) : 3.72min; MS (ES+) gave m/z : 263.1. 1 H-NMR (CDCl 3 ), 6 (ppm) : 2.50 (s, 3H), 3.28 (t, J=7.5, 2H), 4.96 (t, J=7.5, 2H), 7.19-7.25 (211), 7.34 (d, J=7.8, 1H), 7.59-7.64 (211), 7.76 (d, J=8.8, 1H), 8.55 (d, J=4.5, 1H). Example 167 6-(4-(2H-Benzordr1,2,31triazol-2-yl)but-1-ynvl)-N-methylpyridin-2-amine 167(A) (6-Bromo-pyridin-2-vl)-methyl-amine. NaH (150 mg, 3.80 mmol, 60%) was added to a solution of 6-bromo-pyridin-2 ylamine (300 mg, 1.73 mmol) in DMF at 0 C followed by iodomethane (3.47 mL, 6.94 mmol). The reaction mixture was stirred for 1 hour at room temperature and was quenched with water. The aqueous phase was extracted with Et 2 O. The organic phase was washed with water, brine, dried over MgS04, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 90 mg (0.48 mmol, 28%) of (6-bromo-pyridin-2-yl)-methyl-amine. LCMS (RT) : 3.45min; MS (ES+) gave m/z : 189.1. 167(B) 6-(4-(2H-Benzo[d]1,2,31triazol-2-Vl)but-1-ynyl)-N-methvlvpridin-2-amine The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-methyl-amine (105 mg, 0.56 mmol) and 2-but-3-ynyl 2H-benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by C 18 flash chromatography (water to water/acetonitrile 3:2) to yield 22 mg (80 pmol, 14%) of 6-(4-(2H benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-N-methylpyridin-2-amine as a white solid (M.P. = 150-154-C). Rf (cyclohexane/AcOEt 7:3)= 0.2. LCMS (RT) : 2.47min; MS (ES+) gave m/z : 278.2. H-NMR (CDC1 3 ), 8 (PPM) : 2.89 (d, J=5.4, 3H), 3.26 (t, J=7.5, 2H), 4.56-4.67 (br. s, 1H), 4.97 (t, J=7.5, 211), 6.32 (d, J=8.4, 1H), 6.67 (d, J=7.2, 1H), 7.32-7.41 (311), 7.86 (dd, J=3.0 and 6.6, 2H). Example 168 2-(4-(3-(4-Fluorophenl)isoxazol-5-vl)but-1-ynvl)pyridine 168(A) 5-Bromomethv1-3-(4-fluoro-phenvl)-isoxazole The title compound was prepared in accordance with the general method of Example 119(B), from [3-(4-fluoro-phenyl)-isoxazol-5-yl]-methanol (200 mg, 1.03 nmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 250 mg (0.98 nmol, 94%) of 5-bromomethyl-3-(4-fluoro-phenyl)-isoxazole. 168(B) 3-(4-Fluoro-phenvl)-5-(4-trimethylsilanyl-but-3-vnvl)-isoxazole The title compound was prepared in accordance with the general method of Example 107(B), from 5-bromomethyl-3-(4-fluoro-phenyl)-isoxazole (100 mg, 0.39 mmol) to yield 3-(4-fluoro-phenyl)-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (110 mg, 0.38 mmol, 98%) as a brown oil.
WO 2005/123703 PCT/IB2005/002390 184 168(C) 5-But-3-ynvl-3-(4-fluoro-phenvl)-isoxazole The title compound was prepared in accordance with the general method of Example 108(B), from 3-(4-fluoro-phenyl)-5-(4-trimethylsilanyl-but-3-ynyl)-isoxazole (110 mg, 0.38 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 55 mg (0.25 mmol, 67%) of 5-but-3-ynyl-3-(4 fluoro-phenyl)-isoxazole as a white solid. 168(D) 2-(4-(3-(4-Fluorophenvl)isoxazol-5-yl)but-1-vnv1)pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (40 mg, 0.26 mmol) and 5-but-3-ynyl-3-(4-fluoro-phenyl) isoxazole (55 mg, 0.26 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to 7:3) to yield 19 mg (65 pmol, 25%) of 2-(4-(3-(4-fluorophenyl)isoxazol-5-yl)but-1-ynyl)pyridine as a white solid (M.P. = 83-84-C). Rf (cyclohexane/AcOEt 7:3) = 0.2. LCMS (RT) : 4.15min; MS (ES+) gave m/z: 293.2. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.90 (t, J=7.2, 2H), 3.15 (t, J=7.2, 2H), 6.45 (s, 1H), 7.09-7.17 (2H), 7.21 (ddd, J=1.2, 5.1 and 7.5, 1H), 7.36 (d, J=8.1, 1H), 7.58-7.65 (m, 1H), 7.74-7.82 (2H), 8.55 (d, J=4.8, 1H). Example 169 N-(6-(4-(2H-Benzo[dl[1,2.,31triazol-2-Y1)but-l-ynyl)pyridin-2-yl)acetamide 169(A) 6-(4-Benzotriazol-2-Vl-but-1-vnyl)-pyridin-2-Vlamine The title compound was prepared in accordance with the general method of Example 1, from 6-bromo-pyridin-2-ylamine (960 mg, 5.55 mmol) and 2-but-3-ynyl-2H benzo[d][1,2,3]triazole (950 mg, 5.55 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 0.45 g (1.71 nmol, 31%) of 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2 ylamine as a brown solid Rf (cyclohexane/AcOEt 7:3) = 0.2. LCMS (RT) : 2.47min; MS (ES+) gave m/z : 264.2. 169(B) N-(6-(4-(2H-Benzof dl[1,2,31triazol-2-yl)but-1-ynyl)pyridin-2-yl)acetamide A solution of anhydride acetic (34.9 mg, 0.34 mmol) in DCM was added to a solution of 6-(4-benzotiazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (90 mg, 0.34 mmol) and Et 3 N (52 pl, 0.38 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 68 mg (0.22 mmol, 65%) of N-(6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2 yl)acetamide as a white solid (M.P. = 93-94'C). Rf (cyclohexane/AcOEt 3:2) = 0.2. LCMS (RT) : 3.62min; MS (ES+) gave m/z : 306.1. H-NMR (CDC1 3 ), S (ppm) : 2.15 (s, 3H), 3.27 (t, J=7.5, 2H), 4.97 (t, J=7.5, 2H), 7.06 (dd, J=0.6 and 7.5, 1H), 7.38 (dd, J=3.3 and 6.6, 2H), 7.57-7.64 (m, 1H), 7.86 (dd, J=3.0 and 6.6, 2H), 8.13 (d, J=8.4, 1H), 8.15-8.20 (br. s, 1H).
WO 2005/123703 PCT/IB2005/002390 185 Example 170 6-(4-(2H-Benzofdll2,31triazol-2-y1)but-1-yny1)-N-ethylpyridin-2-amine 170(A) (6-Bromo-pyridin-2-y1)-ethyl-amine The title compound was prepared in accordance with the general method of Example 167(A), from 6-bromo-pyridin-2-ylamine (500 mg, 2.89 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5) to yield 280 mg (1.39 mmol, 48%) of (6-bromo-pyridin-2-yl)-ethyl-amine as a colorless liquid. LCMS (RT) : 3.97min; MS (ES+) gave m/z : 202.1. 170(B) 6-(4-(2H-Benzofdl[l,2,31triazol-2-yl)but-1-ynyl)-N-ethylpyridin-2-amine The title compound was prepared in accordance with the general method of Example 1, from (6-bromo-pyridin-2-yl)-ethyl-amine (100 mg, 0.50 mmol) and 2-but-3-ynyl 2H-benzo[d][1,2,3]triazole (0.13 g, 0.75 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 35 mg (0.12 mmol, 24%) of 6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-l ynyl)-N-ethylpyridin-2-amine as a brown solid (M.P. = 73-78'C). Rf (cyclohexane/AcOEt 7:3) = 0.2. LCMS (RT) : 2.77min; MS (ES+) gave m/z: 292.2. 'H-NMR (CDC1 3 ), 8 (ppm) : 1.23 (t, J=7.2, 3H), 2.88 (s, 1H), 2.95 (s, 1H), 3.26 (t, J=7.5, 2H), 4.97 (t, J=7.5, 2H), 6.31 (dd, J=0.6 and 8.4, 1H), 6.66 (dd, J=0.6 and 7.5, 1H), 7.33 (d, J=7.5, 1H), 7.38 (dd, J=0.6 and 6.6, 2H), 7.87 (dd, J=3.0 and 6.6, 2H). Example 171 2-(4-(5-(4-Fluorophenyl)-1H-pyrazol-1-vl)but-1-ynyl)pyridine 171(A) 1-But-3-ynvl-5-(4-fluoro-phenyl)-1H-pyrazole The title compound was prepared in accordance with the general method of Example 109(D), from 5-(4-fluoro-phenyl)-IH-pyrazole (694 mg, 4.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 126 mg (0.59 mmol, 21%) of 1-but-3-ynyl-5-(4-fluoro-phenyl)-1H-pyrazole. 171(B) 2-(4-(5-(4-Fluorophenyl)-lH-pyrazol-1-vl)but-1 -ynl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 360 mg (1.68 mmol) of 1-but-3-ynyl-5-(4-fluoro-phenyl)-1H-pyrazole. The crude residue was purified by flash chromatography (DCM/McOH 99:1) to yield 51 mg (0.17 mmol, 10%) of 2-(4-(5-(4-fluorophenyl)-l1H-pyrazol-1-y)but-1 ynyl)pyridine as a yellow solid. LCMS (RT) : 3.85min; MS (ES+) gave m/z: 292.0. Rf (DCM/MeOH 97:3) = 0.1. Example 172 2-(1 -Fluoro-4-(pyridin-2-yl)but-3-yny1)quinoxaline 172(A) 1-Quinoxalin-2-yl-but-3-yn-1 -ol To a mixture of magnesium (229 mg, 9.41 mmol), mercuric chloride (13 mg, 47 Lmol) and few crystals of iodine in Et 2 O (1.5 mL), a solution of propargyl bromide WO 2005/123703 PCT/IB2005/002390 186 (0.53 mL, 5.88 mmol) in Et 2 O (4.5 mL) was added slowly in order to maintain a reflux. The reaction mixture was stirred 1 hour and added to a solution of quinoxaline 2-carbaldehyde (500 mg, 3.16 mmol) in THF (2 mL). The resulting reaction mixture was stirred at 0 C for 30 min., at room temperature for 30 min. and was poured onto saturated NH 4 C1 solution. The aqueous phase was extracted with Et 2 O. The aqueous phase was washed with water, brine, dried over MgS04, filtered and evaporated. The crude residue was purified by C 18 flash chromatography (H 2 0/acetonitrile 100:0 to 80:20) to yield 90 mg (0.45 mmol, 14%) of 1-quinoxalin-2-yl-but-3-yn-l-ol as a yellow oil. LCMS (RT) : 2.41min; MS (ES+) gave m/z: 199.1. 172(B) 4-Pyridin-2-yl-1-quinoxalin-2-yl-but-3-vn-1-ol The title compound was prepared in accordance with the general method of Example 1, from 2-iodo-pyridine (72 mg, 0.35 mmol) and l-quinoxalin-2-yl-but-3-yn-1-ol (70 mg, 0.35 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2 to DCM/MeOH 9:1) to yield 60 mg (0.22 mmol, 62%) of 4-pyridin-2-yl- 1 -quinoxalin-2-yl-but-3 -yn- 1 -ol. LCMS (RT) : 2.47min; MS (ES+) gave m/z : 276.1. 172(C) 2-(l -Fluoro-4-(pyridin-2-v1)but-3 -vnyl)quinoxaline DAST (19 ptL, 0.15 mmol) was added dropwise to a solution of 4-pyridin-2-yl-1 quinoxalin-2-yl-but-3-yn-l-ol (30 mg, 0.11 mmol) in DCM (1.5 mL) at -78'C. The reaction mixture was stirred for 15 min. at -78 C, quenched by the addition of water at 0 0 C and extracted twice with DCM. The organic phase was washed with water, dried over Na 2
SO
4 , filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 10 mg (36 ptmol, 33%) of 2-(1 fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline as an orange semi-solid with a purity of 70%. LCMS (RT) : 3.55min; MS (ES+) gave m/z: 278.0. 'H-NMR (CDC1 3 ), S (ppm) : 3.20-3.56 (2H), 5.90-6.11 (in, 1H), 7.17-7.22 (m, 1H), 7.31-7.35 (in, 1H), 7.56-7.63 (m, 1H), 7.77-7.83 (2H), 8.07-8.18 (2H), 8.50-8.55 (in, 1H), 9.15 (s, 1H). Example 173 N-(6-(4-(2H-Benzodl[1 ,2,31triazol-2-vl)but-1-ynyl)pyridin-2-vl)methylsulfonamide 173(A) N-Methylsulfonyl-N-[6-(4-benzordl[1,2,31triazol-2-vl-but-1-vnvl)-pyridin-2 yll-methylsulfonamide A solution of methanesulfonyl chloride (98 mg, 0.85 mmol) in DCM was added to a solution of 6-(4-benzotriazol-2-yl-but-1 -ynyl)-pyridin-2-ylamine (100 mg, 0.38 mmol, Example 169(A)) and Et 3 N (0.12 mL, 0.85 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then the solvent was evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 140 mg (0.33 mmol, 88%) of N-methylsulfonyl-N [6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl]-methylsulfonamide as a white solid. LCMS (RT) : 4.00min; MS (ES+) gave m/z: 420.1.
WO 2005/123703 PCT/IB2005/002390 187 173(B) N-(6-(4-(2H-Benzofd1[1,2,31triazol-2-vl)but-1-YnYl)pridin-2 Yllmethylsulfonamide A solution of NaOH (130 mg, 3.30 mmol) in water (3M) was added to a solution of N-methylsulfonyl-N-[6-(4-benzo[d][1,2,3]triazol-2-yl-but-1-ynyl)-pyridin-2-yl] methylsulfonamide (140 mg, 0.33 mmol) in THF (3 mL). The reaction mixture was stirred 4 hours at room temperature. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried over Na 2
SO
4 , filtered and evaporated. Diisopropyl ether was added and the crude product was triturated, filtered and dried to yield 70 mg (0.20 mmol, 62%) of N-(6-(4-(2H-benzo[d][1,2,3]triazol-2 yl)but-1-ynyl)pyridin-2-yl)methylsulfonamide as a white powder (M.P.= 65-68'C). LCMS (RT) : 3.75min; MS (ES+) gave m/z: 342.1. Example 174 2-(4-(3-Methyl-4-phenvl-1H-pyrazol-1-vl)but-1-ynv1)pyridine and 2-(4-(5-methyl-4 phenvl-1H-pyrazol-1-v1)but -nyl)pvridine 174(A) 1-But-3-vnyl-5-methyl-4-phenvl-1H-pvrazole and 1-but-3-ynvl-3-methyl-4 phenyl-1H-pyrazole The title compounds were prepared in accordance with the general method of Example 109(D), from 5-methyl-4-phenyl-1H-pyrazole (515 mg, 3.25 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 255 mg (1.21 mmol, 42%) of 1-but- 3 -ynyl-5-methyl-4-phenyl-1H-pyrazole and 1-but 3-ynyl-3-methyl-4-phenyl-1H-pyrazole. 174(B) 2-(4-(3-Methyl-4-phenvl-1H-pyrazol-1-vl)but-1-vnl)pyridine and 2-(4-(5 methyl-4-phenyl-1H-pyrazol-1-vl but-1-vnvl)pvridine The title compounds were prepared in accordance with the general method of Example 1, from 255 mg (1.21 mmol) of 1-bnt-3-ynyl-5-methyl-4-phenyl-l1H pyrazole and 1-but-3-ynyl-3-methyl-4-phenyl-1H-pyrazole. The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 33 mg (0.11 mol, 10%) of 2-(4-(3-methyl-4-phenyl-l1H-pyrazol-1-yl)but-1-ynyl)pyridine and 2-(4-(5-methyl-4-phenyl-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a orange oil. LCMS (RT) : 3.80min; MS (ES+) gave m/z: 288.0. Rf (DCM/MeOH 98:2) = 0.2. 1 H-NMR (CDC1 3 ), 5 (ppm) : 2.41 (s, 3H), 2.46 (s, 3H), 3.01 (t, J=6.9, 2H), 3.02 (t, J=6.9, 2H), 4.34 (t, J=6.9, 2H), 4.38 (t, 6.9, 2H), 7.20-7.25 (2H), 7.28-7.40 (12H), 7.57-7.63 (4H), 8.55-8.57 (2H). Example 175 N-(6-(4-(2H-Benzo[dl l,2,31triazol-2-yl)but-1-vnYllpyridin-2-vl)formamide A solution of anhydride acetic (0.75 mL) and formic acid (0.32 mL) was heated at 60*C for 3. hours. The reaction mixture was cooled to room temperature, 6-(4 benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (70 mg, 0.27 mmol, 169(A)) was added over 15 min. and the reaction mixture was stirred at room temperature for 1 day. After evaporation of the solvent, the crude residue was triturated with diisopropyl ether, filtered and dried to yield 25 ing (86 tmol, 32%) of N-(6-(4-(2H benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)formamide as a brown solid.
WO 2005/123703 PCT/IB2005/002390 188 LCMS (RT) : 3.3 8min; MS (ES+) gave m/z : 292.1. 1H-NMR (CDC1 3 ), 6 (ppm) : 3.31 (t, J=7.2, 2H), 5.00 (t, J=7.2, 2H), 7.31-7.44,(3H), 7.49 (dd, J=0.6 and 8.1, 1H), 7.72-7.79 (m, 1H), 7.84-7.91 (2H), 9.34 (s, 1H). Example 176 4-Chloro-2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-vnyl)-2H benzordl[1,2,3]triazole The title compound was prepared in accordance with the general method of Example 108(C), from 4-bromo-1,2-dimethyl-1H-imidazole (85 mg, 0.49 mmol) and 2-but-3 ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (100 mg, 0.49 mmol, Example 146(B)). Microwave conditions: 1 00 0 C for 15 min. The crude residue was purified by C 18 flash chromatography to yield 8.0 mg (27 pmol, 5%) of 4-chloro-2-(4-(1,2-dimethyl-1H imidazol-4-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown semi-solid. Rf (cyclohexane/AcOEt 7:3) = 0.2. LCMS (RT) : 2.55min; MS (ES+) gave m/z: 300.2, 302.1. 1 H-NMR (CDC1 3 ), S (ppm) : 2.33 (s, 3H), 3.24 (t, J=7.5, 2H), 3.52 (s, 3H), 4.96 (t, J=7.5, 2H), 6.90 (s, 1H), 7.27-7.34 (m, 1H1), 7.39 (dd, J=0.9 and 7.2,1H), 7.77 (dd, J=0.9 and 8.4, 1H). Example 177 4,5-Dimethyl-2-(4-(pyridin-2-vl)but-3-vnv1)-2H-benzo[d1[1,2,31triazole 177(A) 4,5-Dimethyl-1H-benzoFd1[1,2,31triazole The title compound was prepared in accordance with the general method of Example 127(A), from 3,4-dimethyl-benzene-1,2-diamine (500 mg, 3.67 mmol) to yield 4,5 dimethyl-1H-benzo[d][1,2,3]triazole (520 mg, 3.53 mmol, 95%) as a brown solid. 177(B) 2-But-3-ynyl-4,5-dimethyl-2H-benzord[l1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 4,5-dimethyl-1H-benzo[d][1,2,3]triazole (520 mg, 3.53 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 131 mg (0.66 mmol, 20%) of 2-but-3-ynyl-4,5-dimethyl-2H-benzo[d][1,2,3]triazole. Rf (cyclohexane/AcOEt 4:1)= 0.5. 177(C) 4,5-Dimethyl-2-(4-(pyridin-2-yl)but-3-vnv1)-2H-benzold 1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 2-but-3-ynyl-4,5-dimethyl-2H benzo[d][1,2,3]triazole (75 mg, 0.38 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 65 mg (0.23 mmol, 63%) of 4,5-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as an orange oil. Rf (DCM/MeOH 98:2) = 0.1. LCMS (RT) : 4.05min; MS (ES+) gave m/z: 277.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.39 (s, 3H), 2.57 (s, 3H), 3.27 (t, J=7.5, 2H), 4.96 (t, J=7.5, 2H), 7.19-7.25 (2H), 7.34 (d, J=8.1, 111), 7.58 (d, J=8.7, 1H), 7.58-7.63 (m, 1H), 8.55 (d, J=5.1, 1H).
WO 2005/123703 PCT/IB2005/002390 189 Example 178 2-(4-(6-(Fluoromethyl)pyridin-2-y1)but-3-ynyl)-4,5-dimethyl-2H benzodl[1,2,31triazole The title compound was prepared in accordance with the general method.of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (79 mg, 0.41 mmol) and 2-but-3-ynyl-4,5 dimethyl-2H-benzo[d][1,2,3]triazole (75 mg, 0.38 mmol, 177(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 46 mg (0.15 mmol, 40%) of 2-(4-(6-(fluoromethyl)pyridin-2-y)but-3-yny) 4,5-dimethyl-2H-benzo[d][1,2,3]triazole as an orange oil. Rf (DCM/MeOH 98:2) = 0.1. LCMS (RT) : 4.48min; MS (ES+) gave m/z: 309.1. 1 H-NMR (CDCl 3 ), S (ppm) : 2.40 (s, 3H), 2.58 (s, 3H), 3.27 (t, J=7.5, 2H), 4.95 (t, J=7.5, 2H), 5.40-5.55 (m, 2H), 7.20 (d, J=8.7, 1H), 7.29 (d, J=7.8, 1H), 7.40 (d, J=8.0, 1H), 7.58 (d, J=8.7, lH), 7.66-7.72 (m, 1H). Example 179 2-(4-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-y1)but-1-yny1)pyridine 179(A) 4-(4-Fluoro-phen1)-1H-[l,2,31triazole Sodium azide (4.28 g, 65.8 mmol) was added to a solution (E)-1-fluoro-4-(2-nitro vinyl)-benzene (1.00 g, 5.98 mmol) in DMSO (50 mL), the solution was stirred at room temperature for 14 hours and the reaction mixture was poured onto water. The aqueous phase was extracted with AcOEt. The organic phase was washed with saturated solution of NaHCO 3 , brine, dried over MgSO 4 , filtered and evaporated to yield 300 mg (1.84 mmol, 31%) of 4-(4-fluoro-phenyl)-lH-[1,2,3]triazole. 179(B) 1-But-3-ynvl-4-(4-fluoro-phenyl)-1H-[1,2,31triazole The title compound was prepared in accordance with the general method of Example 109(D), from 4-(4-fluoro-phenyl)-1H-[1,2,3]triazole (306 mg, 1.87 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5 to 90:10) to yield 80 mg (0.37 mmol, 21%) of 1-but-3-ynyl-4-(4-fluoro-phenyl)-lH [1,2,3]triazole. Rf (cyclohexane/AcOEt 4:1) = 0.1. 179(C) 2-(4-(4-(4-Fluoropheny1)-1H-1,2,3-triazol-1-y1)but-1-yny1)pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl) 1H-[1,2,3]triazole (80 mg, 0.37 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 28 mg (96 ptmol, 26%) of 2-(4-(4-(4-fluorophenyl)-lH-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a brown solid (M.P.= 120-122'C). Rf (DCM/MeOH 98.5:1.5) = 0.1. LCMS (RT) : 3.45miu; MS (ES+) gave m/z : 293.1. 1 H-NMR (CDC1 3 ), 5 (ppm) : 3.10 (t, J=6.7, 2H), 4.68 (t, J=6.7, 2H), 7.07-7.14 (m, 2H), 7.22-7.26 (m, 1H), 7.34 (d, J=7.8, 1H), 7.61-7.65 (m, 1H), 7.81 (dd, J=5.1 and 8.7, 2H), 7.97 (s, 1H), 8.58 (d, J=4.5, 1H).
WO 2005/123703 PCT/IB2005/002390 190 Example 180 2-(4-(6-Chloropyridin-2-y1)but-3-ynvll-2fH-benzo[dl[1,2.31triazole The title compound was prepared in accordance with the general method of Example 108(C), from 2,6-dichloropyridine (150 mg, 1.01 mmol) and 2-but-3-ynyl-2H benzo[d][1,2,3]triazole (0.17 g, 1.00 mmol, Example 109(D)). Microwave conditions: 120'C for 15 min. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 15 mg (53 pmol, 5%) of 2-(4-(6-chloropyridin-2 yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid. Rf (cyclohexane/AcOEt 4:1) = 0.2. LCMS (RT) : 4.32min; MS (ES+) gave m/z : 283.1, 285.1. Example 181 2-(4-(6-(Fluoromethvl)pyridin-2-vl)but-3-ynl)-3-methylquinoxaline 181(A) 2-Methyl-3-(4-trimethylsilanyl-but-3-vnvl)-quinoxaline The title compound was prepared in accordance with the general method of Example 118(A), from 2,3-dimethyl-quinoxaline (300 mg, 1.90 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 200 mg (0.74 mmol, 39%) of 2-methyl-3-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline as an orange oil. LCMS (RT) : 5.12min; MS (ES+) gave m/z : 269.1. 181(B) 2-But-3-ynvl-3-methyl-quinoxaline The title compound was prepared in accordance with the general method of Example 108(B), from 2-methyl-3-(4-trimethylsilanyl-but-3-ynyl)-quinoxaline (143 mg, 0.53 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 94:6 to 90:10) to yield 20 mg (0.10 mmol, 19%) of 2-but-3-ynyl-3-methyl quinoxaline as an orange liquid. LCMS (RT) : 3.59min; MS (ES+) gave m/z: 197.1. 181(C) 2-(4-(6-(Fluoromethyl)pyridin-2-v1)but-3-ynyl)-3-methvlquinoxaline The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (24 mg, 0.13 mmol) and 2-but-3-ynyl-3 methyl-quinoxaline (25 mg, 0.13 mmol). Reaction time: 14 hours. The crude residue was purified by preparative chromatography plate (Et 2 O/pentane 7:3) to yield 6.4 mg (21 pmol, 13%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-3 methylquinoxaline as a yellow solid. 'H-NMR (CDC1 3 ), 6 (ppm) : 2.73 (s, 3H), 3.04 (t, J=7.1, 2H), 3.29 (t, J=7.1, 2H), 5.30-5.49 (m, 2H), 7.23 (d, J=7.7, 1H), 7.31 (d, J=7.8, 1H), 7.59-7.65 (3H), 7.91-7.98 (2H). Example 182 2-(4-(6-(1-Fluoroethvl)pvridin-2-vl)but-3-ynyl)-2H-benzoFdl[l.2,31triazole WO 2005/123703 PCT/IB2005/002390 191 182(A) 1-[6-(4-Benzotriazol-2-yl-but-1-ynyl)-pyridin-2-vll-ethanone The title compound was prepared in accordance with the general method of Example 1, from 1-(6-bromo-pyridin-2-yl)-ethanone (500 mg, 2.66 mmol) and 2-but-3-ynyl 2H-benzo[d][1,2,3]triazole (455 mg, 2.66 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 380 mg (1.36 mmol, 51%) of 1-[6-(4-benzotriazol-2-yl-but-1-ynyl) pyridin-2-yl]-ethanone as a white solid. Rf (cyclohexane/AcOEt 7:3)= 0.3. LCMS (RT) : 4.14min; MS (ES+) gave m/z : 279.0. 182(B) 1-[6-(4-Benzotriazol-2-vl-but- 1 -vnyl)-pyridin-2-v11-ethanol NaBH4 (99 mg, 1.6 mmol) was added to a solution of 1-[6-(4-benzotriazol-2-yl-but-1 ynyl)-pyridin-2-yl]-ethanone (380 mg, 1.31 mmol) in MeOH (5 mL) at 0 0 C. The reaction mixture was stirred at room temperature for 30 min., quenched by the addition of water at 0 0 C and extracted twice with DCM. The organic phase was washed with water, dried over Na 2
SO
4 , filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 202 mg (0.69 mmol, 53%) of 1-[6-(4-benzotriazol-2-yl-but- 1 -ynyl)-pyridin-2-yl] -ethanol as a colorless oil. 182(C) 2-(4-(6-(1-Fluoroethyllpyridin-2-yl)but-3-yny1)-2H-benzordl,2,3]triazole The title compound was prepared in accordance with the general method of Example 172(C) from 1-[6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-yl]-ethanol (100 mg, 0.34 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 50 mg (0.17 mmol, 50%) of 2-(4-(6-(1 fluoroethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a colorless oil. Rf (cyclohexane/AcOEt 4:1) = 0.2. LCMS (RT) : 4.28min; MS (ES+) gave m/z : 295.2. 'H-NMR (CDC1 3 ), 5 (ppm) : 1.65 (dd, J=63 and 24.6, 3H), 3.30 (t, J=7.5, 211), 4.99 (t, J=7.5, 2H), 5.53-5.76 (m, 1H), 7.24-7.28 (m, 1H), 7.36-7.43 (3H), 7.63-7.70 (m, 1H), 7.84-7.91 (2H). Example 183 2-(4-(Pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one 183 (A) 2-But-3 -vnvl-2H-isoquinolin- 1-one The title compound was prepared in accordance with the general method of Example 109(D), from 2H-isoquinolin-1-one (200 mg, 1.38 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 125 mg (0.63 mmol, 46%) of 2-but-3-ynyl-2H-isoquinolin-1-one. Rf (DCM/MeOH 99:1)= 0.2. LCMS (RT) : 3.47min; MS (ES+) gave m/z : 198.1. 183(B) 2-(4-(Pyridin-2-vl1but-3-ynvl)isoquinolin-1(2H)-one The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (100 mg, 0.63 mmol) and 2-but-3-ynyl-2H-isoquinolin-l one (120 mg, 0.63 mol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 17 mg (62 pLmol, 10%) of 2 (4-(pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one as a white solid (M.P. = 85-90'C).
WO 2005/123703 PCT/IB2005/002390 192 LCMS (RT) : 3.25min; MS (ES+) gave mI/z: 275.2. 'H-NMR (CDCl3), 5 (ppm) : 2.98 (t, J=6.6, 2H), 4.25 (t, J=6.6, 2H), 6.50 (d, J=7.5, 1H), 7.17-7.23 (m, 1H), 7.32 (d, J=7.8, 1H), 7.42-7.55 (3H), 7.57-7.71 (2H), 8.44 (d, J=8.1, 1H1), 8.55 (d, J=4.8, 111). Example 184 2,6-Dimethoxy-N-methyl-N-(4-(pyridin-2-y1)but-3-ynyl)benzamide 2,6-Dimethoxy-benzoyl chloride (81 mg, 0.41 mmol) was added to a solution of methyl-(4-pyridin-2-yl-but-3-ynyl)-amine (50 ng, 0.31 mmol) and DIEA (69 jiL, 0.41 mmol) in chloroform (2 mL) at 0 C. The reaction mixture was stirred at 0 C for 10 min., at room temperature for 14 hours, quenched by the addition of water and extracted twice with chloroform. The organic phase was washed with saturated solution of NaHCO 3 , brine, dried over MgSO 4 , filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 95:5) to yield 2,6 dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide (12 mg, 37 pmol, 12%). LCMS (RT) : 3.00min; MS (ES+) gave m/z : 325.1. H-NMR (CDC1 3 ), 5 (ppm) : 3.02 (t, J=7.5, 2H), 3.34 (t, J=7.5, 2H), 7.17-7.21 (m, 1H), 7.33 (d, J=7.8, 1H), 7.43 (d, J=8.4, 1H), 7.49-7.54 (in, 1H), 7.58-7.63 (m, 1H), 7.69-7.74 (m, 1H), 7.81 (d, J=8.1, 1H), 8.08 (d, J=8.4; 1H), 8.12 (d, J=8.4, 1H), 8.55 Example 185 2,6-Difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynvl)benzanide The title compound was prepared in accordance with the general method of Example 186, from 2,6-difluoro-benzoyl chloride (51 piL, 0.41 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 95:5) to yield 38 mg (13 ptmol, 40%) of 2,6-difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide. LCMS (RT) : 3.22min; MS (ES+) gave m/z : 301.1. Example 186 N-(2-Fluorophenyl)-5-(pvridin-2-yl)pent-4-ynamide 186(A) N-(2-Fluorophenyl)pent-4-ynamide The title compound was prepared in accordance with the general method of Example 34(A), from 2-fluoro-aniline (566 mg, 5.10 mmol). The crude residue was purified by flash chromatography (DCM) to yield 710 mg (3.71 mmol, 73%) of N-(2 fluorophenyl)pent-4-ynamide as a white solid. LCMS (RT) : 3.33min; MS (ES+) gave m/z : 192.1. Rf (DCM) = 0.2. 186(B) (2-Fluoro-phenyl)pent-4-ynoyl-carbamic acid tert-butyl ester The title compound was prepared in accordance with the general method of Example 34(B), from N-(2-fluorophenyl)pent-4-ynamide (700 mg, 3.66 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 1.08 WO 2005/123703 PCT/IB2005/002390 193 g (3.71 mmol, 100%) of (2-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester as a colourless oil. LCMS (RT) : 4.75min; MS (ES+) gave m/z: 192.1. Rf (cyclohexane/AcOEt 9:1)= 0.3. 186(C) (2-Fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynovl)-carbamic acid tert-butl ester The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (136 mg, 0.86 mmol) and (2-fluoro-phenyl)-pent-4-ynoyl carbamic acid tert-butyl ester (250 mg, 0.86 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 240 mg (0.65 mmol, 76%) of ( 2 -fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid-tert-butyl ester as a white solid. LCMS (RT) : 4.60min; MS (ES+) gave m/z : 369.1. Rf (cyclohexane/AcOEt 4:1) = 0.2. 186(D) N-(2-Fluorophenvl)-5-(pyridin-2-yllpent-4-ynamide The title compound was prepared in accordance with the general method of Example 34(D), from (2-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid-tert-butyl ester (240 mg, 0.65 mmol). After the work-up, the crude residue was washed with diisopropyl ether/pentane 1:1 to yield 120 mg (0.45 mmol, 69%) of N-(2 fluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide as a beige powder (M.P. = 82-84'C). LCMS (RT) : 3.10min; MS (ES+) gave m/z : 269.1. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.75 (t, J=6.9, 2H), 2.87 (t, J=6.9, 2H), 7.00-7.16 (3H), 7.20 (ddd, J=1.2, 5.1 and 7.8, 1H), 7.37 (d, J=7.8,1H), 7.57-7.66 (m, 1H), 7.67-7.77 (m, 1H), 8.24-8.35(m,1H), 8.53 (d, J=4.8, 1H). Example 187 N-(3-Fluorophenyl)-5-(pyridin-2-Vl)pent-4-ynamide 187(A) N-(3-Fluorophenvl)pent-4-ynamide The title compound was prepared in accordance with the general method of Example 34(A), from 3-fluoro-aniline (566 mg, 5.10 mmol). The crude residue was purified by flash chromatography (DCM) to yield 660 mg (3.45 mmol, 68%) of N-(3 fluorophenyl)pent-4-ynamide as a white solid. LCMS (RT) : 3.53min; MS (ES+) gave m/z: 192.1. Rf (DCM) = 0.2. 187(B) (3-Fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butvl ester The title compound was prepared in accordance with the general method of Example 34(B), from N-(3-fluorophenyl)pent-4-ynamide (660 mg, 3.45 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 1.00 g (3.43 mmol) of (3-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester as a colourless oil. LCMS (RT) : 4.68min; MS (ES+) gave m/z: 191.1. Rf (Cyclohexane /AcOEt 9:1) = 0.3. 187(C) (3-Fluoro-phenvl)-(5-pyridin-2-vl-pent-4-ynovl)-carbamic acid tert-butvl ester The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (137 mg, 0.86 mmol) and (3-fluoro-phenyl)-pent-4-ynoyl- WO 2005/123703 PCT/IB2005/002390 194 carbamic acid tert-butyl ester (250 mg, 0.86 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.52 mmol, 60%) of (3-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester as a white solid. LCMS (RT) : 4.48min; MS (ES+) gave m/z: 369.1. Rf (cyclohexane/AcOEt 4:1) = 0.2. 187(D) N-(3-Fluorophenyl)-5-(pyridin-2-v1)pent-4-ynamide The title compound was prepared in accordance with the general method of Example 34(D), from (3-fluoro-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester (190 mg, 0.52 mmol). After the work-up, the crude residue was washed with pentane to yield 125 mg (0.47 mmol, 90%) of N-(3-fluorophenyl)-5-(pyridin-2 yl)pent-4-ynamide as a beige powder (M.P. = 110-1 14C). LCMS (RT) : 3.40min; MS (ES+) gave m/z : 269.1. Example 188 N-(4-Fluoro-2-methyl-phenyl)-5-(pyridin-2-vl)pent-4-ynanide 188(A) N-(4-Fluoro-2-methyl-pheny)pent-4-ynamide The title compound was prepared in accordance with the general method of Example 34(A), from 4-fluoro-2-methyl-phenylamine (638 mg, 5.10 mmol). The crude residue was purified by flash chromatography (DCM) to yield 510 mg (2.49 mmol, 49%) of N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide as a white solid. Rf (DCM) = 0.2. 188(B) (4-Fluoro-2-methyl-phenyl)-pent-4-vnoyl-carbamic acid tert-butyl ester The title compound was prepared in accordance with the general method of Example 34(B), from N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide (500 mg, 2.63 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 790 mg (2.59 mmol) of (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert butyl ester as a colourless oil. Rf (Cyclohexane /AcOEt 9:1) = 0.3. 188(C) (4-Fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert butyl ester The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (129 mg, 0.82 mmol) and (4-fluoro-2-methyl-phenyl)-pent 4-ynoyl-carbamic acid tert-butyl ester (250 mg, 0.82 imnol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.50 mmol, 61%) of (4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent 4-ynoyl)-carbamic acid tert-butyl ester as a white solid. LCMS (RT) : 4.78min; MS (ES+) gave m/z: 382.4. 188(D) N-(4-Fluoro-2-methyl-phenyl)-5-(pvridin-2-yl)pent-4-ynamide The title compound was prepared in accordance with the general method of Example 34(D), from (4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester (220 mg, 0.58 mmol). After the work-up, the crude residue was washed with pentane to yield 85 mg (0.30 imol, 52%) of N-(4-fluoro-2-methyl phenyl)-5-(pyridin-2-yl)pent-4-ynamide as a beige powder (M.P. = 110-1 14'C).
WO 2005/123703 PCT/IB2005/002390 195 LCMS (RT) : 3.13min; MS (ES+) gave m/z : 283.1. Example 189 2,6-Dichloro-N-(4-(6-(fluoromethyl)pridin-2-y)but-3-ynvl)benzamide 189(A) 2-( 4 -(Trimethylsilyl)but-3-ynyl)isoindoline-1,3-dione The title compound was prepared in accordance with the general method of Example 109(D), from 4-(trimethylsilyl)but-3-yn-1-ol (3.20 g, 22.5 mmol) and phthalimide (3.50 g, 23.8 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 3.1 g (11 mmol, 51%) of 2-(4-(trimethylsilyl)but-3 ynyl)isoindoline-1,3-dione as a white solid. 189(B) 2-(But-3-ynllisoindoline-1,3-dione The title compound was prepared in accordance with the general method of Example 108(B), from 2-( 4 -(trimethylsilyl)but-3-ynyl)isoindoline-1,3-dione (3.10 g, 11.4 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 985 mg (4.94 mmol, 43%) of 2-(but-3-ynyl)isoindoline-1,3-dione as a white solid. 189(C) 2
-(
4
-(
6 -(Fluoromethyllpyridin-2-vl)but-3-vnylisoindoline-1,3-dione The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (336 mg, 1.77 mmol, Example 190(E)) and 2-(but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.61 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 320 mg (1.04 mmol, 65%) of 2
-(
4 -(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as a white solid. LCMS (RT) : 3.97min; MS (ES+) gave m/z: 309.1. 189(D) 4-(6-(Fluoromethyl)pyridin-2-v1)but-3-yn-1-amine Hydrazine hydrate (1.0 mL, 5.2 mmol) was added to a solution of 2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.04 mmol) in EtOH (3 mL) and the reaction mixture was stirred for 4 hours at 50'C. The mixture was cooled down, DCM was added and the aqueous phase was extracted. The organic phase was washed with saturated solution of NaHCO 3 , dried over Na 2
SO
4 , filtered and concentrated to yield 117 mg (0.66 mmol, 63%) of 4-(6-(fluoromethyl)pyridin-2 yl)but-3 -yn- 1-amine as a white solid. 189(E) 2,6-Dichloro-N-(4-(6-(fluoromethl)pyridin-2-yl)but-3-nyllbenzamide The title compound was prepared in accordance with the general method of Example 184, from 4 -(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39 mg, 0.22 mmol) and 2,6-dichlorobenzoyl chloride (60 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 21 mg (0.06 mmol, 27%) of 2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide as a yellow oil. LCMS (RT) : 3.72min; MS (ES+) gave m/z: 351.0, 3.53.0. Example 190 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-iH-benzo[dlimidazole WO 2005/123703 PCT/IB2005/002390 196 190(A) (1-Methyl-iH-benzordlinidazol-2-yl)methanol A solution of 1-methyl-1H-benzo[d]imidazole-2-carbaldehyde (473 mg, 2.95 mmol) in MeOH (0.3 M, 10 mL) was cooled at 0 0 C before the addition in small portions of NaBH 4 (559 mg, 14.80 mmol). After 90min at 0 0 C, the reaction mixture was quenched with saturated NaHCO 3 , extracted twice with Et 2 O. The combined organic layers were washed with saturated brine and dried over MgSO 4 . The solvent was removed under reduced pressure to afford 418 mg of 1-methyl-1H-benzo[d]imidazol 2-yl)methanol (Yield: 87%) as a white solid. The crude product was used in the next step without any further purification. Rf (DCM/MeOH: 95/5)= 0.19 190(B) 2-(Chloromethyl)-1-methyl-lH-benzo [dlimidazole 1-Methyl-1H-benzo[d]imidazol-2-yl)methanol (418 mg, 2.58 mmol) was partially dissolved in DCM (2 mL). At room temperature thionyl chloride (12.90 mmol, 0.935 mL) was added in one portion to the resulting suspension. The reaction mixture was stirred at room temperature for 90min. The solvent was removed under reduced pressure to give a yellow solid. The solid was poured into saturated NaHCO 3 and extracted twice with Et 2 O. The combined organic layers were washed with saturated brine and dried over MgSO 4 . The solvent was removed under reduced pressure and the crude product was purified by Flash chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 97/3 as eluent) to afford 380 mg of 2 (chloromethyl)-l-methyl-1H-benzo[d]imidazole (Yield: 81%) as a white-pink solid. Rf (DCM/MeOH: 95/5) = 0.50 190(C) 1 -Methyl-2-(4-(trimethylsilyIlbut-3-yny1)-1H-benzo[dliniidazole The title compound was prepared in accordance with the general method of Example 67(D), from trinethyl(prop-1-ynyl)silane (283 mg, 2.52 mmol) and 2-(chloromethyl) 1-methyl-lH-benzo[d]imidazole (380 mg, 2.10 mmol). The crude product was purified over prepacked 25 g silicagel column (DCM/MeOH from 100/0 to 98/2 as eluent) to afford 317 mg of 1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H benzo[d]imidazole (Yield: 59%) as red solid. Rf (DCM/MeOH: 98/2)= 0.37 LCMS (RT) : 3.25 min; MS (ES+) gave m/z : 257.2 190(D)2-(But-3-ynyl)-l-methyl-1H-benzo[dlimidazole According to the protocol described in Example 38(D), the conversion of 1-methyl-2 (4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (317 mg, 1.23 mmol) afforded 146 mg of 2-(but-3-ynyl)-l-methyl-1H-benzo[d]imidazole (Yield : 64%) as yellow orange solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: 99/1 as eluent). LCMS (RT) : 0.65-1.93min; MS (ES+) gave m/z : 185 Rf (DCM/MeOH: 95/5) = 0.29 190(E) 2-Bromo-6-(fluoromethyl)pyridine A solution of (6-bromopyridin-2-yl)methanol (5 g, 27 mmol) in dry DCM (60 mL) was added dropwise at -78'C to a cooled solution of DAST (13 g, 80 mmol) in dry DCM (50 mL). The reaction mixture was stirred lh at -78'C then lh at room temperature. To complete the reaction, an additional 5 mL of DAST were slowly WO 2005/123703 PCT/IB2005/002390 197 added at -60'C and the reaction mixture was kept overnight at room temperature. The reaction was quenched with water and the organic layer extracted with DCM, dried over MgSO 4 and evaporated. Purification over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt: 90/10 as eluent) to afford 4.50 g of 2-bromo-6 (fluoromethyl)pyridine (Yield: 89%) as pale yellow oil which crystallized at 0 0 C. LCMS (RT) : 3.42min; MS (ES+) gave m/z : 191,192 Rf (Cyclohexane/AcOEt: 90/10) = 0.4 'NMR (CDC1 3 ), S (ppm) : 7.60-7.50 (in, 1H), 7.40-7.30 (m, 2H), 5.55-5.25 (d, 2H) 190(F) 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H benzoldlimidazole In a dry microwave tube were placed in suspension CuI (7.55 mg, 0.039 mmol) and triethylamine (1.45 mL, 10.30 nnnol). Then under nitrogen atmosphere, were added the 2-bromo-6-(fluoromethyl)pyridine (151 mg, 0.79 mmol), PdC1 2 (PPh 3
)
2 (27.80 mg, 0.039 mmol) and triphenyl phosphine polymerbound (41.6 mg, 0.158 mmol). The suspension was stirred at room temperature for few minutes, finally the 2-(but-3 ynyl)-l-methyl-l1H-benzo[d]imidazole (146 mg, 0.792 mmol) in 1.1 mL of DMF was added, and the reaction mixture was stirred at room temperature for 30min. The reaction mixture was stirred and heated under micro wave irradiation for 15min at 120'C. After filtering to remove triphenyl phosphine polymerbound, the triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NaHCO 3 , H20 and saturated brine. The organic layer was dried over Na 2 S04, filtered and concentrated. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: from 100/0 to 98.5/1.5 as eluent) to afford 127 mg of 2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole as a yellow solid (Mp = 95.3-96.3'C). Rf (DCM/MeOH: 95/5) = 0.13 LCMS (RT) : 2.41min ; MS (ES+) gave m/z : 294 'H-NMR (CDC1 3 ), S (ppm) : 7.80-7.65 (in, 2H), 7.45-7.20 (in, 5H), 5.60-5.38 (d, 2H), 3.80 (s, 3H), 3.30-3.20 (in, 2H), 3.15-3.05 (m, 2H). Example 191 7--Chloro-2-(4-(6-(fluoromethvl)pyridin-2-vl)but-3-vnvl)-1-methv1-1H benzo[dlimidazole 191(A) 2-Chloro-N-methyl-6-nitrobenzenamine 2-Fluoro-3-chloronitrobenzene (3.0 g, 17 mmol) was dissolved in EtOH (6 mL) and Methylamine 40% in Water (6 mL) was added dropwise at 0 0 C and mixture was warmed up to RT overnight. Mixture went to a dark orange precipitate within 10min. The solid was isolated by filtration, rinsed with water (2*10 mL) and dried in a desiccators under vacuum to afford 3 g of 2-chloro-N-methyl-6-nitrobenzenamine (Yield: 90%) as an orange crystalline solid. Rf (Cyclohexane/EtOAc: 80/20) = 0.52 LCMS (RT) : 4.29min WO 2005/123703 PCT/IB2005/002390 198 191(B) 6-Chloro-NI-methylbenzene-1,2-diamine 2-Chloro-N-methyl-6-nitrobenzenamine (1.5 g, 8.0 mmol) was dissolved in a mixture of EtOH (15 mL) and H 2 0 (15 ml). Iron powder (2.2 g, 40 mmol) was added followed by Acetic acid (0.55 mL, 9.6 mmol). The reaction was monitored by TLC, after 30min, the reaction was completed. The reaction mixture was filtered over celite pad and the filtrate was neutralized by saturated NaHCO 3 (10 mL). The product was extracted by EtOAc (2*10 mL), the organic layer was washed with brine (10 mL), dried over MgSO 4 and concentrated to dryness to afford 920 mg of 6-chloro-N 1 methylbenzene-1,2-diamine (Yield: 73%) as dark brown oil. Rf (Cyclohexane/EtOAc: 70/30) = 0.51 LCMS (RT) : 2.18min 191(C) 7-Chloro-2-(chloromethvl)-1-methyl-1H-benzordlimidazole 6-Chloro-N 1 -methylbenzene-1,2-diamine (800 mg, 5 mmol) and 2-chloroacetic acid (700 mg, 8 mmol) were dissolved in HCl 2N (5.7 mL). The resulting solution was heated at 90'C for 18h. The aqueous layer was neutralized by 3N NaOH. After' extraction with EtOAc (3 * 10 mL), the organic layer was washed with water (10 mL), brine (10 mL) and dried over Na 2
SO
4 . The solvent was removed under reduced pressure and the resulting crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : 70/30 as eluent) to afford 478 mg of 7-chloro-2-(chloromethyl)-l-methyl-lH-benzo[d]imidazole (Yield : 40%) as a pink solid Rf (DCM/MeOH: 95/5)= 0.35 LCMS (RT) : 3.70min ; MS (ES+) gave m/z : 217 191(D) 7-Chloro-1-methyl-2-(4-(trimethvlsilv1Tbut-3-vnyl)-1H-benzo~dlimidazole To a solution of the trimethyl(prop-1-ynyl)silane (0.21 mL, 1.4 mmol) in THF (4 mL), was added at -78'C nBuLi 2.5M in hexane (0.56 mL, 1.3 mmol). After 90min at 78'C, a solution of 7-chloro-2-(chloromethyl)-1-methyl-1IH-benzo[d]imidazole (250 mg, 1.2 mmol) in THF (2 mL) was added. Mixture went from purple to orange and then dark brown. The reaction was quenched after 1h at -78'C with water and the solvent was evaporated to dryness to afford 338 mg of 7-chloro-l-methyl-2-(4 (trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (Yield : 100%) as a brown oily solid. It was carried through to the next step without purification. LCMS (RT): 4.43min; MS (ES+) gave m/z : 291 191(E) 2-(But-3-ynvl)-7-chloro-1-methyl-1H-benzofdlimidazole According to the protocol described in Example 38(D), the conversion of 7-chloro-1 methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (338 mg, 1.16 mmol) afforded 116 mg of 2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (Yield 45%) as orange-brown oily solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent). LCMS (RT) : 2.68min; MS (ES+) gave m/z : 219 Rf (Cyclohexane/AcOEt: 70/30) = 0.17 191(F) 7-Chloro-2-(4-(6-(fluoromethl)pyridin-2-l)but-3-vnv)-1 -methyl-1H benzo[dlimidazole The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (30 mg, 0.16 mmol) and 2-(but-3- WO 2005/123703 PCT/IB2005/002390 199 ynyl)-7-chloro-l-methyl-1H-benzo[d]imidazole (35 mg, 0.16 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 99/1 as eluent) to afford 43 mg of a light brown solid. The resulting solid was triturated into isopropyl ether to give 6 mg of 7-chloro-2-(4 (6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl-1H-benzo[d]imidazole (Yield 10%) as white solid. LCMS (RT) : 3.25min; MS (ES+) gave m/z : 328 Rf (DCM/MeOH: 95/5) =0.30 Example 192 7-Chloro-1-methyl-2-(4-(pyridin-2-yl)but-3-vnyl)-1H-benzofdlimidazole In a dry reaction tube containing copper iodide (1 mg, 0.0055 mmol) and triethylamine (0.50 mL, 0.1 mmol), were added 2-iodopyridine (22 mg, 0.11 mmol) and Pd(PPh 3
)
2 Cl 2 (2.4 mg, 0.0055 mmol). A yellow suspension was obtained and after a few minutes of stirring at room temperature, 2-(but-3-ynyl)-7-chloro-l-methyl-1H benzo[d]imidazole (compound 191(E), 24 mg, 0.11 mmol) in triethylamine (0.2 mL) was added. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30min and then at 50'C for 3h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH 4 Cl, water and brine. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography system (prepacked silicagel column 2 g, DCM/MeOH : 98/2 as eluent) to afford 2 mg g of 7-chloro-l-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H benzo[d]imidazole (Yield: 6%) as brown solid. LCMS (RT) : 2.84min; MS (ES+) gave m/z: 296 Rf (DCM/MeOH: 95/5) = 0.30 Example 193 4,6-Difluoro-2-(4-(6-(fluorometh1)pyridin-2-yl)but-3-ynvl)-1-methyl-1H benzo[dlimidazole 193(A) 3,5-Difluoro-N-methyl-2-nitrobenzenanine 1,3,5-Trifluoro-2-nitrobenzene (3.0 g, 16.90 mmol) was dissolved in EtOH (29.7 mL) and Methylamine 40% in Water (1.44 mL, 17.80 mmol) was added dropwise at 0 0 C. The color went from bright yellow to an orange precipitate within 20min. After 4h at RT. 0.66 mL of Methylamine -was added (9 mmol). To complete the reaction, an additional 0.26 ml (3.6 mmol) of Methylamine was added after 2h at RT. The completion was achieved within 20min. Water (75 mL) was added to the reaction mixture and the solid was isolated by filtration, washed with water (2*10 mL) and dried over high vacuum to afford 2.64 g of 3,5-difluoro-N-methyl-2-nitrobenzenamine (Yield: 83%) as an orange solid. Rf (Cyclohexane/EtOAc: 70/30) 0.57 LCMS (RT) : 4.13min 193(B) 3,5-Difluoro-N-methylbenzene-1,2-diamine The title compound was prepared in accordance with the general method of Example 191(B), from 3,5-difluoro-N-methyl-2-nitrobenzenamine (1.5 g, 8 mmol) to afford WO 2005/123703 PCT/IB2005/002390 200 933 mg of 3,5-difluoro-NI'-methylbenzene-1,2-diamine (Yield: 74%) as a deep purple oily liquid. Rf (DCM/MeOH : 95/5) =0.66 193(C) 2-(Chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[dlimidazole The title compound was prepared in accordance with the general method of Example 191(C), from 3,5-difluoro-N -methylbenzene-1,2-diamine (1.50 g, 9.50 mmol) and 2 chloroacetic acid (1.3 g, 14 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 70/30 as eluent) to afford 443 mg of 2-(chloromethyl)-4,6-difluoro-1-methyl-1H benzo[d]imidazole (Yield : 22%) as a purple solid. LCMS (RT) : 3.46min; MS (ES+) gave m/z: 217 Rf (DCM/MeOH: 95/5) =0.43 193(D) 4,6-Difluoro-1-methyl-2-(4-(trimethylsilyl)but-3-vnyl)-1H-benzordlimidazole The title compound was prepared in accordance with the general method of Example 191(D), from 2-(chloromethyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (440 mg, 2.03 mmol) and trimethyl(prop-l-ynyl)silane (274 mug, 2.44 mmol). 4,6-difluoro 1-methyl-2-(4-(trimethylsilyl)but-3-yny)-1H-benzo[d]imidazole (539 mg, Yield : 91%) was obtained as a brown oil which can be used in the next step without any purification. LCMS (RT): 4.67min; MS (ES+) gave m/z: 293 193(E) 2-(But-3-yv11-4,6-difluoro-1-methyl-1H-benzo[dlimidazole According to the protocol described in Example 38(D), the conversion of 4,6 difluoro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-lH-benzo[d]imidazole (539 mg, 1.84 mmol) afforded 126 mg of 2-(but-3-ynyl)-4,6-difluoro-l-methyl-lH benzo[d]imidazole (Yield : 31%) as an orange solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : from 80/20 to 70/30). LCMS (RT) : 3.22min; MS (ES+) gave m/z: 221 193(F) 4,6-Difluoro-2-(4-(6-(fluoromethl)pyridin-2-vl)but-3-vnvl)-1-methv1-1H benzordlinidazole The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (109 mg, 0.57 mol) and 2-(but-3 ynyl)-4,6-difluoro-1-methyl-1H-benzo[d]imidazole (126 mg, 0.57 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH : from 100/0 to 99/1 as fluent) to afford 43mg of a light brown solid. The resulting solid was dissolved in Dioxane and 0.5N HC1 in dioxan was added (0.14 mL, 0.07 mmol). A green solid was formed and it was collected by filtration and washed with AcOEt. The chlorhydrate salt was dissolved in MeOH, neutralized by saturated NaHCO 3 . The aqueous layer was extracted twice with AcOEt. The organic layer was dried over MgSO 4 and the solvent removed under reduced pressure to afford 9 mg of 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-1-methyl 1H-benzo[d]imidazole (Yield: 5%) as purple oily solid (Mp = 103'C-104'C). LCMS (RT) : 3.68niin; MS (ES+) gave m/z: 330 Rf (DCM/MeOH: 95/5) =0.36 WO 2005/123703 PCT/IB2005/002390 201 'IH-NMR (CDCl 3 ), 6 (ppm) : 7.70-7.60 (t, 1H), 7.40-7.30 (d, 111), 7.30-7.20 (d, 1H), 6.80-6.60 (in, 2H), 5.46-5.31 (d, 2H), 3.68 (s, 3H), 3.18-3.12 (in, 2H), 3.02-2.95 (in, 2H) Example 194 1-Isopropyl-2-(4-(pyridin-2-vl)but-3-vnvl)-1H-benzordlimidazole 194(A) N-Isopropyl-2-nitrobenzenamine To a solution of 1-fluoro-2-nitrobenzene (4.406 g, 31.22 mmol) in EtOH (32 mL) was added at 0 0 C isopropyl amine (2.97 mL, 32.80 mmol). The mixture turned from light yellow to bright orange instantly. It was stirred overnight at RT. Another 1eq of isopropyl amine (2.97 mL, 32.80 mmol) was added and after 3h of stirring 2eq of isopropyl amine were added (6 mL, 64 mmol) and the resulting solution was kept at room temperature overnight. The reaction mixture was concentrated and another equivalent of isopropyl amine was added (2.97 mL) following by EtOH (2 mL). For completion, the reaction was heated at 50'C for 2h. Mixture was evaporated to dryness and dissolved in EtOAc (25 mL) and the oraganic phase was washed with water (3*10 mL). Aqueous phase was re-extracted with EtOAc (10 mL) and the combined organics were washed with brine and dried over Na 2
SO
4 . The solvent was evaporated under reduced pressure to afford 5.24 g of N-isopropyl-2 nitrobenzenamine (Yield: 93%) as an orange liquid Rf (Cyclohexane/AcOEt: 70/30) =0.67 LCMS (RT) : 4.58min 194(B) N'-Isopropylbenzene-1,2-diamine The title compound was prepared in accordance with the general method of Example 191(B), from N-isopropyl-2-nitrobenzenamine (5.24 g, 29.1 mmol) to afford 3.88 g of N'-isopropylbenzene-1,2-diamine (Yield: 89%) as a dark brown liquid. Rf (Cyclohexane/AcOEt : 70/30) =0.36 LCMS (RT): 1.68min; MS (ES+) gave m/z: 151 194(C) 2-(Chloromethyl)-1-isopropv1-1H-benzo[dlimidazole The title compound was prepared in accordance with the general method of Example 191(C), from N 1 -isopropylbenzene-1,2-diamine (3.88 g, 25.82 mmol) and 2 chloroacetic acid (3.70 g, 39 mmol). The crude residue was purified over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt : 70/30 as eluent) to afford 2.05 g of 2-(chloromethyl)-1-isopropyl-1H-benzo[d]imidazole (Yield 38%) as a light brown oil. LCMS (RT) : 2.88min; MS (ES+) gave m/z: 209 Rf (Cyclohexane/AcOEt: 70/30) =0.27 IH-NMR (CDC1 3 ), S (ppm) : 7.74-7.64 (in, 1H), 7.55-7.45 (m, 1H), 7.25-7.16 (m, 2H), 4.80-4.70 (in, 3H), 1.64-1.55 (d, 6H). 194(D) 1-Isopropyl-2-(4-(trimethylsilvl)but-3-ynvl)-1H-benzoldlimidazole The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-l-isopropyl-lH-benzo[d]imidazole (500 mg, 2.4 mmol) and trimethyl(prop-1-ynyl)silane (323 mg, 2.88 mmol). 1-isopropyl-2-(4 (trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (680 mg, Yield : 100%) was obtained as a brown oil which was used in the next step without any purification.
WO 2005/123703 PCT/IB2005/002390 202 LCMS (RT) : 3.27min; MS (ES+) gave m/z: 285 194(E) 2-(But-3-ynyl)-1-isopropyl-1H-benzofdlimidazole According to the protocol described in Example 38(D), the conversion of 1 -isopropyl 2-(4-(trimethylsilyl)but-3-yny)-1H-benzo[d]imidazole (680 mg, 2.39 mmol) afforded 84 mg of 2-(but-3-ynyl)-1-isopropyl-1IH-benzo[d]imidazole (Yield : 17%) as an orange solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30). LCMS (RT): 2.32min; MS (ES+) gave m/z: 213 'H-NMR (CDCl 3 ), 5 (ppm) : 7.75-7.63 (m, 1H), 7.54-7.43 (in, 1H), 7.27-7.15 (in, 2H), 4.70-4.63 (m, 1H), 3.14-3.00 (in, 2H), 2.81-2.74 (in, 2H), 1.92 (s, 1H), 1.66-1.55 (d, 6H). 194(F) 1-Isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzoFdlimidazole The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (81 mg, 0.39 mmol) and 2-(but-3-ynyl)-1-isopropyl-1H benzo[d]imidazole (84 mg, 0.39 nimol). The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH : from 100/0 to 96/4 as eluent) to afford 47 mg of 1-isopropyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H benzo[dlimidazole as a light brown oil (Yield : 41%). LCMS (RT) : 2.42min; MS (ES+) gave m/z: 290 'H-NMR (CDCl 3 ), 5 (ppm) : 8.55-8.45 (d, 1H), 7.80-7.05 (in, 7H), 4.80-4.57- (in, 1H), 3.30-2.92 (in, 4H), 1.69-1.50 (d, 6H). Example 195 1-Phenethyl-2-(4-(pyridin-2-yl)but-3-nyl)-1 H-benzofdlimidazole 195(A) 2-Nitro-N-phenethylbenzenamine To a solution of 1-fluoro-2-nitrobenzene (4.4 g, 31.2 mmol) in EtOH (32 mL) was added at 0 0 C, 2-phenylethanamine (4.11 mL, 32.8 mmol). Mixture went from light yellow to bright orange instantly and it was stirring overnight at RT. Another equivalent of 2-phenylethanamine was added (4.11 mL, 32.8 mmol) and the mixture was heated to 50'C overnight. Water was added (20 ml) and the resulting orange solid was isolated by filtration to afford 6.99 g of 2-nitro-N-phenethylbenzenamine (Yield: 92%) as an orange crystaline solid. LCMS (RT) : 4.95min; MS (ES+) gave m/z: 243 195(B) I'-Phenethylbenzene-1,2-diamine The title compound was prepared in accordance with the general method of Example 191(B), from 2-nitro-N-phenethylbenzenamine (6.99 g, 28.9 mmol) to afford 5.66 g of N-phenethylbenzene-1,2-diamine (Yield: 92%) as a brown oily solid. Rf (Cyclohexane/AcOEt: 70/30) =0.41 LCMS (RT) : 3.03min; MS (ES+) gave m/z : 213 195(C) 2-(Chloromethyl)-1-phenethyl-1H-benzofdlimidazole The title compound was prepared in accordance with the general method of Example 191(C), from N 1 -phenethylbenzene-1,2-diamine (2.57 g, 12.11 mmol) and 2 chloroacetic acid (1.70 g, 18 mmol). The crude residue was purified over silicagel WO 2005/123703 PCT/IB2005/002390 203 chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt : from 80/20 to 70/30 as fluent) to afford 2.02 g of 2-(chloromethyl)-l-phenethyl-1H benzo [d]imidazole (Yield: 61%) as a white crystalline solid. LCMS (RT) : 3.88min; MS (ES+) gave m/z : 271 Rf (Cyclohexane/AcOEt : 70/30) 0.18 195(D) 1-Phenethyl-2-(4-(trimethlsilvllbut-3-vny1)-1H-benzordlimidazole The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-l-phenethyl-1H-benzo[d]imidazole (500 mg, 1.8 mmol) and trimethyl(prop-1-ynyl)silane (249 mg, 2.22 mmol). 1-phenethyl-2-(4 (trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (639 mg, Yield : 100%) was obtained as a brown oil which was used in the next step without purification. LCMS (RT) : 3.90min; MS (ES+) gave m/z: 347 195(E) 2-(But-3-yn11-1-phenethyl-1H-benzo[dlimidazole According to the protocol described in Example 38(D), the conversion of 1 phenethyl-2-(4-(trimethylsilyl)but-3-ynyl)-l1H-benzo[d]imidazole (639 mg, 1.84 mmol) afforded 62 mg of 2-(but-3-ynyl)-l-phenethyl-1H-benzo[d]imidazole (Yield: 12%) as an orange oily solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : 70/30). LCMS (RT) : 3.07min; MS (ES+) gave m/z : 275 'H-NMR (CDC 3 ), S (ppm) : 7.70-7.63 (m, 1H), 7.28.7.12 (m, 6H), 7.27-7.15 (m, 2H), 4.35-4.25 (t, 2H), 3.08-2.95 (t, 2H), 2.65-2.55 (m, 4H), 1.90 (s, 1H). 195(F) 1-Phenethyl-2-(4-(pyridin-2-vl)but-3-ynyl)-lH-benzofd~imidazole The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (46 mg, 0.22 mmol) and 2-(but-3-ynyl)-1-phenethyl-1H benzo[d]imidazole (62 mg, 0.22 mmol). The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH : from 100/0 to 96/4 as fluent) to afford 20 mg of 1-phenethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H benzo[d]imidazole as a light brown oil (Yield: 25%). LCMS (RT) : 3.00min; MS (ES+) gave m/z : 352 'H-NMR (CDC1 3 ), S (ppm) : 8.50-8.45 (d, 1H), 7.72-7.65 (m, 1H), 7.58-7.48 (t, 1H), 7.31-7.10 (m, 8H), 6.93-6.86 (m, 2H), 4.37-4.25 (t, 2H), 3.08-2.95 (t, 2H), 2.86-2.68 (m, 4H). Example 196 1-Benzyl-2-(4-(pyridin-2-yl)but-3-vnvl)-1H-benzo[dlimidazole 196(A) N-Benzyl-2-nitrobenzenamine The title compound was prepared in accordance with the general method of Example 195(A), from phenylmethanamine (3.51 g, 32.78 mmol) and 1-fluoro-2-nitrobenzene (4.40 g, 31.22 mol). 6.65 g of N-benzyl-2-nitrobenzenamine (Yield : 93%) was obtained as an orange crystalline solid which was used without further purification. LCMS (RT) : 3.70min; MS (ES+) gave m/z : 229 196(B) N-Benzvlbenzene-1,2-dianine WO 2005/123703 PCT/IB2005/002390 204 The title compound was prepared in accordance with the general method of Example 191(B), from N-benzyl-2-nitrobenzenamine (6.65 g, 29.1 mol) to afford 4.66 g of N benzylbenzene-1,2-diamine (Yield : 80%) as a brown oil which was used in the next step without further purification. Rf (Cyclohexane/AcOEt : 70/30) =0.45 LCMS (RT) : 2.83min; MS (ES+) gave m/z: 199 196(C) 1-Benzyl-2-(chloromethyl)-l1H-benzofdlimidazole The title compound was prepared in accordance with the general method of Example 191(C), from N'-benzylbenzene-1,2-diamine (2.93 g, 14.78 mmol) and 2-chloroacetic acid (2.10 g, 22 mmol). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt : from 80/20 to 70/30 as eluent) to afford 2.34 g of 1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole (Yield: 61%) as a yellow oil. LCMS (RT) : 3.87min; MS (ES+) gave m/z : 257 Rf (Cyclohexane/AcOEt : 70/30) =0.28 196(D) 1-Benzyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[dlimidazole The title compound was prepared in accordance with the general method of Example 191(D), from of 1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole (500 mg, 1.9 mmol) and trimethyl(prop-1-ynyl)silane' (262 mg, 2.34 mmol). 1-benzyl-2-(4 (trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (647 mg, Yield : 100%) was obtained as a brown oil which was used in the next step without purification.. LCMS (RT) : 3.83min; MS (ES+) gave m/z: 333 196(E) 1-Benzv1-2-(but-3-ynyl)-1H-benzo[dlimidazole According to the protocol described in Example 38(D), the conversion of 1-benzyl-2 (4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (647 mg, 1.94 mmol) afforded 41 mg of 1-benzyl-2-(but-3-ynyl)-1H-benzo[d]iinidazole (Yield : 8%) as orange oily solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30). LCMS (RT) : 2.80min; MS (ES+) gave m/z : 261 'H-NMR (CDC1 3 ), 8 (ppm) : 7.75-7.63 (in, 1H), 7.30.7.10 (m, 7H), 7.00-6.95 (in, 1H), 5.30 (s, 2H), 3.05-2.95 (t, 2H), 2.70-2.80 (t, 2H), 1.92 (s, 1H) 196(F) 1-Benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[dlimidazole The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (38 mg, 0.18 miol) and 1-benzyl-2-(but-3-ynyl)-1H benzo[d]imidazole (49 mg, 0.18 minmol). The crude residue was purified over silicagel chromatography (prepacked 2 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 15 ing of 1-benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H benzo[d]imidazole as a yellow oily solid (Yield : 23%). LCMS (RT) : 2.90min; MS (ES+) gave m/z: 338 'H-NMR (CDC1 3 ), 5 (ppm) : 8.50 (d, 1H), 7.70-7.65 (d, 1H), 7.55-7.44 (t, 1H), 7.25 7.05 (in, 8H), 7.00-6.88 (in, 2H), 5.30 (s, 2H), 3.14-3.07 (in, 2H), 3.05-2.92 (m, 2H) WO 2005/123703 PCT/IB2005/002390 205 Example 197 5-Fluoro-1-methyl-2-(4-(pyridin-2-y)but-3-vnv1)-1H-benzo[dlimidazole 1.97(A) 4-Fluoro-N-methyl-2-nitrobenzenamine 1,4-Difluoro-2-nitrobenzene (2.63 g, 16.53 mmol) was dissolved in EtOH (9 mL) and Methylamine 40% in Water (9 mL) was added dropwise at 0 0 C and the mixture was warming up to RT overnight. 75 mL of water was added to the reaction mixture and the orange solid was filtered and washed with water (2*10 ml) to afford 2.78 g of 4 fluoro-N-methyl-2-nitrobenzenamine (Yield: 99%) as an orange crystaline solid. Rf (Cyclohexane/AcOEt: 80/20) =0.34 LCMS (RT) : 4.03min; MS (ES+) gave m/z : 171 197(B) 4-Fluoro-N'-methylbenzene-1,2-diamine The title compound was prepared in accordance with the general method of Example 191(B), from 4-fluoro-N-methyl-2-nitrobenzenamine (1.5 g, 8.8 mmol) to afford 1.08 g of 4-fluoro- N'-methylbenzene-1,2-diamine (Yield: 88%) as a brown oil which was used in the next step without purification. Rf (DCM/MeOH: 95/5) =0.61 LCMS (RT) : 0.84min; MS (ES+) gave m/z : 141 197(C) 2-(Chloromethv1)-5-fluoro-1-methyl-1H-benzo[dlimidazole The title compound was prepared in accordance with the general method of Example 191(C), from 4-fluoro-N'-methylbenzene-1,2-diamine (2.5 g, 17.84 mmol) and 2 chloroacetic acid (2.50 g, 27 mmol). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt : 60/40 as eluent) to afford 277 mg of 2-(chloromethyl)-5-fluoro-1-methyl-lH benzo[d]imidazole (Yield: 8%) as a semi-solid. LCMS (RT) : 2.88min; MS (ES+) gave m/z: 199 Rf (DCM/MeOHl: 95/5) =0.29 197(D) 5-Fluoro-1-methyl-2-(4-(trimethvlsilvl)but-3-vnvl)-lH-benzordlimidazole The title compound was prepared in accordance with the general method of Example 191(D), from of 2-(chloromethyl)-5-fluoro-1-methyl-iH-benzo[d]inidazole (270 mg, 1.36 mmol) and trimethyl(prop-l-ynyl)silane (183 mg, 1.63 mmol). The crude residue was used in the next step without any purification. 5-fluoro-l-methyl-2-(4 (trimethylsilyl)but-3-ynyl)-l1H-benzo[d]imidazole (373 mg, Yield: 100%) as a brown oil. LCMS (RT): 3.37min; MS (ES+) gave m/z : 275 Rf (DCM/MeOH: 95/5) =0.36 197(E) 2-(But-3-vnyl)-5-fluoro-1-methyl-1H-benzo[dlimidazole According to the protocol described in Example 38(D), the conversion of 5-fluoro-1 methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]im-idazole (373 mg, 1.35 mmol) afforded 73 mg of 2-(but-3-ynyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (Yield 26%) as an orange solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : from 80/20 to 70/30). LCMS (RT): 1.85min; MS (ES+) gave m/z : 203 WO 2005/123703 PCT/IB2005/002390 206 'H-NMR (CDCl 3 ), 5 (ppm) : 7.40-6.95 (m, 3H), 3.70 (s, 3H), 3.10-3.00 (m, 2H), 2.80 2.70 (m, 2H), 1.95 (m, 1H) 197 (F) 5-Fluoro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzoFdlimidazole The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (74 mg, 0.36 mmol) and 2-(but-3-ynyl)-5-fluoro-1 methyl-1H-benzo[d]imidazole (73 mg, 0.36 mmol). The crude residue was purified over silicagel chromatography (prepacked 2 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 28 mg of 5-fluoro-1-methyl-2-(4-(pyridin-2-yl)but 3-ynyl)-1H-benzo[d]imidazole as a orange oily solid (Yield: 27%). LCMS (RT) : 2.35min; MS (ES+) gave m/z : 280 Rf (DCM/MeOH: 95/5) =0.37 'H-NMR (CDC1 3 ), S (ppm) : 8.50 (d, 1H), 7.62-7.50 (t, 1H), 7.33-7.25 (m, 2H), 7.18 7.05 (m, 2H), 7.00-6.90 (t, 1H), 3.70 (s, 3H), 3.22-3.11 (m, 2H), 3.02-2.95 (m, 2H) Example 198 1-(4-(Pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one 198(A) 4-Bromobut-1-yny1trimethylsilane To a solution of 3-butyn-1-ol (4 g, 57 mmol) in THF (0.7M, 80 mL)) at -78'C was added 2.1N n-BuLi in hexane (52 mL, 110 mmol). After 1h at -78'C, the reaction mixture was treated with chlorotrimethylsilane (13 g, 120 mmol) and the resulting mixture was warmed to room temperature over 2h. The reaction mixture was quenched with water, extracted with Et 2 O, and concentrated. The concentrate was treated with HCI 3N, extracted with Et 2 O (3x), washed with saturated aqueous NaHCO 3 (3x) and NaCl (lx), dried (MgSO 4 ), and concentrated. The crude product was diluted in THF (50 mL), the solution was cooled to -78'C before the addition of 26 mL of n-BuLi 2.1N in hexane (52 mmol.). After 1h at -78'C p-toluenesulfonyl chloride (12 g, 63 mmol.) in THF solution (35 mL) was added. The reaction mixture was stirred over night at room temperature. The reaction mixture was treated with water, followed by extraction with ether, washing with saturated aqueous NaHCO 3 , with NaCl, dried (MgSO 4 ) and concentrated The crude product was dissolved in acetone (100 mL) containing LiBr (5 g, 57 mmol.) and the reaction mixture was stirred at room temperature for 5h. The reaction mixture was poured into water. Extraction with pentane (4x), washing with saturated aqueous NaHCO 3 and NaCl, drying (MgSO 4 ), concentration to give 7.50 g of 4-bromobut-1-ynyl)trimethylsilane (Yield : 64%) as a brown oil which was used in the next step without further purification. 198(B) 1-(But-3-yny1)pyridin-2(lH)-one 4-bromobut-1-ynyl)trimethylsilane (700 mg, 3 mmol), pyridin-2-ol (300 mg, 3 mmol) and K 2 C0 3 (900 mg, 6 mmol) were poured into acetone (4.2 ml) and the resulting mixture was heated in the microwave at 150'C for 7min. The solvent was evaporated and the crude product was dissolved DCM and the organic layer was washed with water. The crude residue was purified over silicagel chromatography (prepacked 5 g silicagel column, DCM/MeOH : 99/1 as fluent) to afford 33 mg of 1-(but-3 ynyl)pyridin-2(1H)-one as a brown oil (Yield: 5%). LCMS (RT) : 2.20min; MS (ES+) gave m/z: 148 Rf (DCM/MeOH : 95/5) =0.19 WO 2005/123703 PCT/IB2005/002390 207 'H-NMR (CDCl 3 ), S (ppm) : 7.35-7.25 (m, 211), 6.55-6.45 (d, 1H), 6.15-6.05 (t, 1H), 4.00-3.93 (t, 2H), 2.58-2.64 (m, 2H), 1.95-1.90 (t, 1H) 198(C) 1-(4-(Pyridin-2-v1)but-3-vnv1)pyridin-2(lH)-one The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (50 mg, 0.2 mmol) and l-(but-3-ynyl)pyridin-2(1H)-one (33 mg, 0.2 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 97/3 as eluent) to afford 10 mg of 1-(4-(pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one as a yellow oil (Yield : 20%). LCMS (RT) : 2.22min; MS (ES+) gave m/z: 225 'H-NMR (CDC1 3 ), S (ppm) : 8.55-8.45 (m, 1H), 7.62-7.50 (t, 1H), 7.41-7.12 (m, 4H), 6.55-6.45 (m, 1H), 6.10-6.05 (t, 1H), 4.10-4.05 (t, 2H), 2.90-2.80 (t, 2H) Example 199 3-Methoxv-N-methyl-N-(4-(pyridin-2-yl)but-3-ynv1)benzanide 199(A) 4-(Pyridin-2-v1)but-3-yn-1-ol To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2 bromopyridine (5 g, 31.6 mmol), followed by Pd 2 C1 2 (PPh 3
)
2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0 0 C under N 2 , 3-butyn-l-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70'C. The reaction mixture was quenched at 0 0 C with water, TEA was removed under low pressure, and the organic layer was extracted 3x using DCM, washed with Ammonia, water, brine, dried over MgSO 4 , filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH : from 99/1 to 95/5 as eluent) to afford 3.60 g of 4 (pyridin-2-yl)but-3-yn-l-ol as a brown oil (Yield: 77%). LCMS (RT) : 1.58min; MS (ES+) gave m/z: 148 Rf (DCM/MeOH : 95/5) =0.23 199(B) 4-(Pyridin-2-yl)but-3-vnvl methanesulfonate To a stirred solution of 4-(pyridin-2-y)but-3-yn-1-ol (3.60 g, 24 mmol) in dry methylene chloride (30 mL) was added triethylamine (4.40 mL, 32 mmol). The mixture was cooled at 4'C and methanesulfonyl chloride (2.50 mL, 32 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was then poured over ice/water (100 mL) and stirred for 5 min. To this mixture was added saturated aqueous sodium bicarbonate solution (50 mL) chilled to 4'C, and the mixture was stirred for 30 min, then extracted with DCM. The combined organic fractions were dried over MgS04, filtered and concentrated under pressure to afford 4.60 g of 4-(pyridin-2-yl)but-3-ynyl methanesulfonate (Yield : 83%) as a brown oil which can be used in the next step without further purification. LCMS (RT) : 2.43min; MS (ES+) gave m/z : 226 Rf (DCMIMeOH: 95/5) =0.6 199(C) N-Methv1-4-(pyridin-2-v1)but-3-n-1 -amine 4-(Pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 12.87 mmol) was dissolved in methylamine 40% in aqueous solution (20 mL) and stirred for 3 hoursunder nitrogen WO 2005/123703 PCT/IB2005/002390 208 at 451C. The reaction mixture was cooled with ice, quenched with water and extracted with DCM. The organic phases were washed with brine, dried over MgSO 4 and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH : from 90/10 to 90/10 with 1% of TEA as eluent) to afford 817 mg N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (Yield: 39%) as a brown oil LCMS (RT) : 0.65min; MS (ES+) gave m/z: 161 1H-NMR (CDC1 3 ), 6 (ppm) : 8.55-8.52 (m, 1H), 7.58-7.68 (t, 1H), 7.43-7.38 (d, 1H), 7.23-7.18 (d, 1H), 2.90-2.82 (t, 2H), 2.70-2.63 (t, 211), 2.48 (s 3H) 199(D) 3-Methoxy-N-methyl-N-(4-(pyridin-2-vl)but-3-ynv1)benzamide N-Methy-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 nnol) was dissolved in DCM (2 mL) and DIEA (67 pl, 0.41 mmol) was added at room temperature. The resulting mixture was cooled to 0 0 C before the addition of 3-methoxybenzoyl chloride (69 mg, 0.41 mmol). After stirring overnight at room temperature, the mixture was quenched with water and extracted with DCM. DCM fractions were washed with water (10 mL), NaHCO 3 sat (2*10 mL), water (10 mL), brine (10 mL). The solvent was removed and the crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 95/5 as eluent) to afford 58 mg of 3-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide (Yield: 63%) as a brown oil. LCMS (RT) : 3.17min; MS (ES+) gave m/z : 295 'H-NMR (CDC1 3 ), 6 (ppm) 2 conformers A/B=57/43 ratio : 8.56-8.44 (m, 1H), 7.64 7.52 (m, 2H), 7.36-7.08 (m, 2H), 6.96-6.80 (in, 3H), 3.80-3.65 (s, 3H and m, 2H, conformer A), 3.75-3.40 (t, 2H, conformers B), 3.10-2.98 (2s, 3H, conformer A and B), 2.85-2.70 (t, 2H, conformer A), 2.65-2.50 (t, 2H, conformer B) Example 200 3-Fluoro-N-methyl-N-(4-(pyridin-2-vl)but-3-ynv1)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3 fluorobenzoyl chloride (64 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 97/3 as eluent) to afford 34 mg of 3-fluoro-N-methyl-N-(4-(pyridin-2-yl)but 3-ynyl)benzamide as a brown oil (Yield : 39%). LCMS (RT) : 3.21min; MS (ES+) gave m/z : 283 Rf (DCM/MeOH: 95/5) =0.22 1 H-NMR (CDC1 3 ), 5 (ppm) 2 conformers A/B=60/40 ratio: 8.55-8.45 (d, 1H), 7.62 7.50 (t, 1H), 7.35-7.22 (m, 2H), 7.18-6.95 (m, 4H), 3.78-3.63 (s, 2H, conformer A), 3.60-3.50 (s, 2H,conformer B), 3.10-2.95 (2s, 3H conformers A+B), 2.85-2.70 (s, 2H, conformer A), 2.68-2.50 (s, 2H, conformer B) Example 201 N-Methyl-2-phenl-N-(4-(pridin-2-l)but-3-nl)acetamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2- WO 2005/123703 PCT/IB2005/002390 209 phenylacetyl chloride (60 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 97/3 as eluent) to afford 64 mg of N-methyl-2-phenyl-N-(4-(pyridin-2 yl)but-3-ynyl)acetamide as a brown oil (Yield : 74%). LCMS (RT) : 3.15min; MS (ES+) gave m/z: 279 'H-NMR (CDC1 3 ), 5 (ppm) 2 conformers A/B=63/37 ratio : 8.55-8.45 (m, 1H), 7.62 7.52 (t, 1H), 7.38-7.12 (m, 7H), 3.80 (s, 2H, conformer B), 3.70 (s, 2H, conformer A), 3.65-3.55 (m, 2H), 3.10 (s, 3H, conformer A), 2.95 (s, 3H, conformer B), 2.70 (t, 2H, conformer A), -2.53 (t, 2H, conformer B) Example 202 N-Methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-l-amine (50 mg, 0.31 mmol) and 2 (trifluoromethyl)benzoyl chloride (80 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 97/3 as eluent) to afford 63 mg of N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl) 2-(trifluoromethyl)benzamide as a brown oil (Yield: 61%). LCMS (RT) : 3.57min; MS (ES+) gave m/z : 333 'H-NMR (CDC1 3 ), 6 (ppm) 2 conformers A/B=65/35 ratio: 8.55-8.45 (d, 1H), 7.65 7.10 (m, 7H), 3.90-.3.60 (m, 2H, conformer A), 3.45-3.20 (m, 2H, conformer B), 3.10 (s, 3H, conformer B), 2.85 (s, 3H, conformer A), 2.80-2.70 (m, 2H, conformer A), 2.60-2.50 (m, 2H, confomer B). Example 203 4-Fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyllbenzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 4-fluorobenzoyl chloride (99 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : 98/2 as eluent) to afford 103 mg of 4-fluoro-N-methyl-N-(4-(pyridin-2-y)but-3 ynyl)benzamide as a brown oil (Yield: 58%). LCMS (RT) : 3.03min; MS (ES+) gave m/z: 283 Rf (DCM/MeOH: 95/5) =0.41 'H-NMR (CDC1 3 ), 8 (ppm) : 8.55-8.45 (m, 1H), 7.65-7.58 (m, 1H), 7.48-7.32 (m, 3H), 7.23-7.18 (m, 1H), 7.10-7.02 (m, 2H), 3.85-3.50 (m, 2H), 3.10 (s, 3H), 2.90-2.60 (m, 2H). Example 204 2-Chloro-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-l-amine (100 mg, 0.62 mmol) and 2-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : 98/2 as WO 2005/123703 PCT/IB2005/002390 210 eluent) to afford 118 mg of 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3 ynyl)benzamide as a brown oil (Yield : 63%). LCMS (RT) : 3.20min; MS (ES+) gave m/z : 299 Rf (DCMIMeOH : 95/5) =0.42 'H-NMR (CDC1 3 ), 8 (ppm) 2 conformers A/B=59/41 ratio: 8.55-8.45 (m, 1H), 7.65 7.58 (t, 1H), 7.43-7.15 (m, 6H), 3.95-3.40 (m, 2H), 3.20 (s, 3H, conformer B), 2.95 (s, 3H, conformer A), 2.90-2.83 (m, 2H, conformer A), 2.68-2.60 (m, 2H, conformer B). Example 205 3-Chloro-N-methyl-N-(4-(pyridin-2-vl)but-3-ynvl)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 3-chlorobenzoyl chloride (109 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : 98/2 as eluent) to afford 112 mg of 3-chloro-N-methyl-N-(4-(pyridin-2-y)but-3 ynyl)benzamide as a brown oil (Yield: 60%). LCMS (RT) : 3.35min; MS (ES+) gave m/z : 299 Rf (DCM/MeOH: 95/5) =0.42 'H-NMR (CDC1 3 ), 6 (ppm) 2 conformers A/B=63/37 ratio: 8.55-8.45 (m, 1H), 7.60 7.50 (t, 1H), 7.40-7.10 (m, 6H), 3.90-3.70 (m, 2H, conformer A), 3.60-3.50 (m, 2H, conformer B), 3.05 (s, 3H), 2.90-2.80 (m, 2H, conformer A), 2.75-2.60 (m, 2H, conformer B). Example 206 4-Fluoro-N-methvl-N-(4-(pyridin-2-vl)but-3-yny1)benzenesulfonamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (100 mg, 0.62 mmol) and 4-fluorobenzene-l-sulfonyl chloride (121 mg, 0.62 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : 98/2 as eluent) to afford 32 mg of 4-fluoro-N-methyl-N-(4-(pyridin-2 yl)but-3-ynyl)benzenesulfonamide as a yellow oil (Yield: 16%). LCMS (RT) : 3.70min; MS (ES+) gave m/z : 319 1H-NMR (CDC1 3 ), 6 (ppm) : 8.55-8.45 (m, 1H), 7.85-7.75 (t, 2H), 7.60-7.50 (t, 1H), 7.30 (d, 1H), 7.20-7.00 (m, 3H), 3.30-3.20 (t, 2H), 2.80 (s, 3H), 2.70-2.60 (m, 2H). Example 207 2-Chloro-N-methyl-N-(4-(pyridin-2-Vl)but-3-ynvl)benzenesulfonamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-l-amine (50 mg, 0.31 mmol) and 2 chlorobenzene-l-sulfonyl chloride (79 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 37 mg of 2-chloro-N-methyl-N (4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brown oil (Yield: 35%). Rf (DCM/MeOH: 95/5) =0.51 WO 2005/123703 PCT/IB2005/002390 211 LCMS (RT) : 3.78min; MS (ES+) gave m/z : 335 'H-NMR (CDC1 3 ), 6 (ppm) : 8.55-8.45 (in, 1H), 8.15-8.05 (d, 1H), 7.68-7.60 (t, 1H), 7.55-7.35 (in, 411), 7.23-7.15 (m, 111), 3.60-3.50 (t, 2H), 3.00 (s, 3H), 2.80-2.70 (t, 2H). Example 208 2-Chloro-N-(4-(6-(fluoromethv1)pyridin-2-vl)but-3-ynv1)-N-methylbenzamide 208(A) 4-(6-(Fluoromethvl)pyridin-2-v1)but-3-yn-1-ol The title compound was prepared in accordance with the general method of Example 199(A), from 2-bromo-6-(fluoromethyl)pyridine (compound 190(E), 3.50 g, 18 minol) and 3-butyn-1-ol (1.3 g, 18 mmol). The crude residue was purified over silicagel chromatography (prepacked 85 g silicagel column, DCM/MeOH : from 100/0 to 9//3 as eluent) to afford 2.60 g of 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn 1-ol as an orange solid (Yield: 79%). Rf (DCM/MeOH: 95/5) =0.31 LCMS (RT) : 2.52min; MS (ES+) gave m/z : 180 208(B) 4-(6-(Fluoromethv1pyridin-2-vl)but-3-vnvl methanesulfonate The title compound was prepared in accordance with the general method of Example 199(B), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-l-ol (2.60 g, 15 mmol) and methanesulfonyl chloride (1.50 mL, 19 mmol) to afford 2.90 g of 4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate (Yield : 78%) as a pale yellow oil which was used in the next step without further purification. Rf (DCM/MeOH : 95/5) =0.60 LCMS (RT) : 3.28min; MS (ES+) gave m/z: 258 208C) 4-(6-(FluoromethvL)pyridin-2-vl)-N-methylbut-3-vn-1-amine The title compound was prepared in accordance with the general method of Example 199(C), from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 11 mmol) and N-methylamine 40% in aqueous solution (20 mL). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to 90/10 with 1% TEA as eluent) to afford 324 mg of 4-(6 (fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine as a pale oil (Yield : 15%). LCMS (RT) : 0.65-71.83min; MS (ES+) gave m/z: 193 208(D) 2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-vl)but-3-vnv1)-N-methylbenzamide The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36 mmol) and 2-chlorobenzoyl chloride (76 mg, 0.44 mmol).. The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 37 mg of 2-chloro-N-(4-(6 (fiuoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a brown oil (Yield 31%). LCMS (RT) : 3.82min; MS (ES+) gave m/z: 331 Rf (DCM/MeOH: 95/5) =0.25 1 H-NMR (CDC1 3 ), 5 (ppm) 2 conformers A/B=61/39 ratio: 7.75-7.65 (t, 1H), 7.45 7.23 (in, 6H), 5.60-5.35 (2d, 2H, conformer A+B), 3.95-3.70 (m, 2H, conformer A), WO 2005/123703 PCT/IB2005/002390 212 3.50-3.40 (m, 2H, conformer B), 3.20 (s, 3H, conformer B), 2.95 (s, 3H, conformer A), 2.90-2.82 (t, 2H, conformer A), 2.70-2.60 (t, 2H, conformer B) Example 209 2-Chloro-N-(4-(6-(fluoromethvl)pyridin-2-vl)but-3-vnyl)-N-methylbenzene sulfonamide The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36 mmol) and 2-chlorobenzene-1-sulfonyl chloride (92 mg, 0.44 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, Cyclohexane/AcOEt : 70/30 as eluent) to afford 41 mg of 2-chloro-N-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzenesulfonamide as a yellow oil (Yield: 3 1%). Rf (Cyclohexane/AcOEt : 70/30) =0.26 LCMS (RT) : 4.30min; MS (ES+) gave m/z: 367 1 H-NMR (CDC1 3 ), 5 (ppm) : 8.10 (d, 1H), 7.75-7.65 (t, 1H), 7.52-7.30 (m, 5H), 5.53 5.38 (d, 2H), 3.60-3.50 (t, 2H), 3.00 (s, 3H), 2.80-2.70 (t, 2H) Example 210 2,6-Dichloro-N-(4-(6-(fluoromethv1)pvridin-2-yl)but-3-yny1)-N-methylbenzamide The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (180 mg, 0.93 mmol) and 2,6-dichlorobenzoyl chloride (255mg, 1.22 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 18.5 mg of 2,6-dichloro-N-(4 (6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a yellow oil (Yield :5%). Rf (Cyclohexane/AcOEt: 70/30) =0.26 LCMS (RT) : 3.93 and 4.04min; MS (ES+) gave m/z : 365 'H-NMR (CDC1 3 ), 6 (ppm) 2 conformers A/B=90/10 ratio: 7.75-7.65 (t, 1H), 7.48 7.20 (in, 5H), 5.60-5.35 (2d, 2H, comformers A+B), 3.80-3.70 (t, 2H, comformer A), 3.50-3.40 (t, 2H, conformer B), 3.22 (s, 3H, conformer B), 2.98 (s, 3H, conformer A), 2.95-2.85 (t, 2H, conformer A), 2.75-2.65 (t, 2H, conformer B) Example 211 N-Methv1-N-(4-(pyridin-2-yl)but-3-yny1)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and benzoyl chloride (53 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as fluent) to afford 30 ing of N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamideas a brown oil (Yield : 36%). Rf (DCM/MeOH : 95/5) =0.31 LCMS (RT) : 2.92min; MS (ES+) gave m/z: 265 WO 2005/123703 PCT/IB2005/002390 213 'H-NMR (CDC1 3 ), 5 (ppm) 2 conformers A/B=59/41 ratio: 8.55-8.45 (in, 1H), 7.60 7.50 (t, 1H), 7.40-7.10 (in, 7H), 3.80-3.60 (in, 2H, conformer A), 3.55-3.40 (m, 2H, conformer B), 3.15-3.10 (2s, 3H), 2.85-2.70 (in, 2H, conformer A), 2.65-2.50 (in, 2, conformer B). Example 212 N,2-Dimethyl-N-(4-(pyridin-2-yl)but-3-vnvI)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-tmethyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2 methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 32.5 ing of N,2-dimethyl-N-(4-(pyridin-2-yl)but-3 ynyl)benzamideas a brown oil (Yield: 3 7%). LCMS (RT) : 3.15min; MS (ES+) gave m/z : 279 Rf (DCM/MeOH: 95/5) =0.33 'H-NMR (CDC1 3 ), 6 (ppm) 2 conformers A/B=59/41 ratio: 8.55-8.45 (in, 1H), 7.60 7.50 (t, 1H), 7.30-7.10 (in, 6H), 3.90-3.70 (in, 2H, conformer A), 3.40-3.30 (t, 2H, conformer B), 3.15 (s, 3H, conformer B), 2.90 (s, 3H, conformer A), 2.85-2.75 (t, 2H, conformer A), 2.60-2.50 (t, 2H, conformer B), 2.25-2.15 (2s, 3H, conformer A+B) Example 213 2-Fluoro-N-methyl-N-(4-(pyridin-2-vl)but-3-ynyl)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-l-amine (50 mg, 0.31 mmol) and 2 fluorobenzoyl chloride (59 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 28 mg of 2-fluoro-N-methyl-N-(4-(pyridin-2-yl)but 3-ynyl)benzamide as a brown oil (Yield: 32%). LCMS (RT) : 3.00min; MS (ES+) gave m/z: 283 Rf (DCM/MeOH : 95/5) =0.33 'H-NMR (CDC1 3 ), 6 (ppm) 2 conformers A/B=57/43 ratio: 8.55-8.45 (in, 1H), 7.70 7.60 (t, 1H), 7.45-7.30 (in, 3H), 7.25-7.05 (in, 3H), 3.88-3.75 (t, 2H, conformer A), 3.55-3.45 (t, 2H, conformer B), 3.20 (s, 3H, conformer B)-3.00 (s, 3H, conformer A), 2.90-2.80 (t, 2H, conformer A), 2.70-2.60 (t, 2H, conformer B). Example 214 N,4-Dimethv1-N-(4-(pyridin-2-vl)but-3-yny1)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 4 methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 31 mg of N,4-dimethyl-N-(4-(pyridin-2-yl)but-3 ynyl)benzaniideas a brown oil (Yield: 3 6%). Rf (DCM/MeOH: 95/5) =0.35 WO 2005/123703 PCT/IB2005/002390 214 LCMS (RT) : 3.28min; MS (ES+) gave m/z : 279 'H-NMR (CDC1 3 ), 5 (ppm) 2 conformers A/B=58/42 ratio: 8.55-8.45 (m, 1H), 7.70 7.60 (t, 1H), 7.40-7.15 (m, 6H), 3.85-3.70 (m, 2H, conformer A), 3.65-3.50 (m, 2H, conformer B), 3.10 (s, 3H), 2.92-2.80 (m, 2H, conformer A), 2.78-2.60 (m, 2H, conformer B), 2.35 (s, 3H) Example 215 N,3-Dimethyl-N-(4-(pyridin-2-vl)but-3-ynyl)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3 methylbenzoyl chloride (58 mg, 0.37 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 25 mg of N,3-dimethyl-N-(4-(pyridin-2-y)but-3 ynyl)benzamide as a yellow pale oil (Yield: 29%). LCMS (RT) : 3.37min; MS (ES+) gave m/z : 279 Rf (DCM/MeOH: 95/5) =0.36 'H-NMR (CDCl 3 ), 6 (ppm) 2 conformers A/B=55/45 ratio: 8.55-8.45 (m, 1H), 7.60 7.50 (t, 1H), 7.35-7.10 (m, 6H), 3.80-3.70 (m, 2H, conformer A), 3.55-3.40 (m, 2H, conformer B), 3.10-3.00 (s, 3H, conformer A+B), 2.80-2.70 (m, 2H, conformer A), 2.65-2.50 (m, 2H, conformer B), 2.25 (s, 3H) Example 216 2-Methoxy-N-methl-N-(4-(pyridin-2-l)but-3-yny1)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-l-amine (50 mg, 0.31 mmol) and 2 methoxybenzoyl chloride (69 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as fluent) to afford 71 mg of 2-methoxy-N-methyl-N-(4-(pyridin-2 yl)but-3-ynyl)benzamide-as a green-brown oil (Yield: 77%). LCMS (RT) : 3.08min; MS (ES+) gave m/z : 295 Rf (DCMIMeOH: 95/5) =0.39 1 H-NMR (CDCl 3 ), 6 (ppm) 2 conformers A/B=50/50 ratio: 8.55-8.45 (n, 1H), 7.68 7.58 (t, 1H), 7.42-7.18 (m, 4H), 7.00-6.88 (m, 2H), 3.90-3.80 (m, 4H), 3.50-3.40 (m, 1H), 3.20 (s, 3H, conformer A), 2.95 (s, 3H, conformer B), 2.90-2.80 (t, 2H, conformer A), 2.70-2.60 (t, 2H, conformer B). Example 217 2,3-Difluoro-N-methyl-N-(4-(pyridin-2-vl)but-3-ynyl)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-l-amine (50 ing, 0.31 mmol) and 2,3-difluorobenzoyl chloride (72 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 67 mg of 2,3-difluoro-N-methyl-N-(4-(pyridin-2 yl)but-3-ynyl)benzamide as a brown oil (Yield: 71%).
WO 2005/123703 PCT/IB2005/002390 215 LCMS (RT) : 3.32min; MS (ES+) gave m/z : 301 Rf (DCM/MeOH : 95/5) =0.28 'H-NNR (CDC1 3 ), 6 (ppm) 2 confonners A/B=60/40 ratio: 8.55-8.45 (m, 1H), 7.60 7.50 (t, 1H), 7.35-7.20 (m, 1H), 7.20-7.00 (m, 4H), 3.80-3.70 (t, 2H, conformer A), 3.50-3.40 (t, 2H, conformer B), 3.15 (s, 3H, conformer B), 2.95 (s, 3H, conformer A), 2.80-2.70 (t, 2H, conformer A), 2.65-2.50 (t, 2H, conformer B). Example 218 2,6-Dichloro-N-methl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 47 mg of 2,6-dichloro-N-methyl-N-(4-(pyridin-2 yl)but-3-ynyl)benzamide as a brown oil (Yield: 45%). Rf (DCM/MeOH: 95/5) =0.38 LCMS (RT) : 3.53min; MS (ES+) gave m/z : 333 1 H-NMR (CDCl 3 ), 6 (ppm) 2 conformers AIB=71/29 ratio: 8.55-8.45 (m, 1H), 7.60 7.50 (t, 1H), 7.30-7.10 (in, 5H), 3.80-3.70 (t, 2H, conformer A), 3.40-3.30 (t, 2H, conformer B), 3.15 (s, 3H, conformer B), 2.90 (s, 3H, conformer A), 2.85-2.75 (t, 2H, conformer A), 2.70-2.60 (t, 2H, conformer B). Example 219 N,3,5-Trimethyl-N-(4-(pyridin-2-ylbut-3-ynyl)isoxazole-4-sulfonamide The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3,5-dimethylisoxazole-4-sulfonyl chloride (79 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 17 mg of N,3,5-trimethyl-N-(4 (pyridin-2-yl)but-3 -ynyl)isoxazole-4-sulfonamide as a brown oil (Yield: 17%). Rf (DCM/MeOH : 95/5) =0.42 LCMS (RT) : 3.47min; MS (ES+) gave m/z : 320 'H-NMR (CDCl 3 ), 8 (ppm) : 8.60-8.50 (d, 1H), 7.70-7.60 (t, 1H), 7.40-7.30 (d, 1H), 7.30-7.15 (m, 1H), 3.50-3.40 (t, 2H), 2.93 (s, 3H), 2.80-2.70 (t, 2H), 2.65 (s, 3H), 2.40 (s, 3H) Example 220 N-(4-(Pyridin-2-vl)but-3-vnvl)benzo[dlthiazol-2-amine 220(A) 4-(Pyridin-2-yl)but-3-vn- 1 -amine To a solution of 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione (compound 3(B), 6.81 g, 34 mmol) in ethanol (20 m-L, 0.3M) was added 6.6 miL of hydrazine hydrate 25%. The reaction mixture was heated 4 hoursat 50'C. The awaited product was formed and the starting material was completely consumed. The reaction mixture was WO 2005/123703 PCT/IB2005/002390 216 washed twice with NaHCO 3 saturated, and the organic layer was dried, filtrated and concentrated. Purification by flash chromatography reverse phase (C18 column, pack 35 g, with
H
2 0/Acetonitrile : 95/5 as fluent), to afford 814 mg of 4-(pyridin-2-yl)but-3-yn-1 amine (Yield: 82%) as yellow solid. 220(B) N-(4-(Pyridin-2-yl)but-3-nyl)benzo[dlthiazol-2-amine 4-(pyridin-2-yl)but-3-yn-1-amine (640 mg, 4.40 mmol), 2-cblorobenzo[d]thiazole (373 mg, 2.2 nnol) and DIEA (452 tL, 2.64 mmol) wre poured into DMF (2.2 mL) and the resulting solution was heated two days at 120'C. The solvent was removed under reduce pressure and the crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : 70/30 as eluent) to afford 582 mg of N-(4-(pyridin-2-y)but-3-yny)benzo[d]thiazol-2-amine (Yield : 95%) as a brownish oil. LCMS (RT) : 3.09min; MS (ES+) gave m/z : 280 Rf (Cyclohexane/AcOEt: 70/30) =0.30 Example 221 I-Methyl-3-(5-(pyridin-2-yllpent-4-yny)-1H-benzo[dlimidazol-2(3H)-one 221(A) 2-(5-Chloropent-l -yn1)pyridine The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromopyridine (948 mg, 6.0 mmol) and 5-chloropent-1-yne (620 mg, 6.0 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : from 100/0 to 80/20 as eluent) to afford 655 mg of 2-(5-chloropent-1-ynyl)pyridine as a yellow oil (Yield: 61%). LCMS (RT) : 3.56min; MS (ES+) gave m/z : 180 Rf (Cyclohexane/AcOEt: 80/20) =0.30 221(B) 1 -Methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-1H-benzordlimidazol-2(3H)-one 2-(5-chloropent-1-ynyl)pyridine (59 mg, 0.33 mmol), 1-methyl-1H-benzo[d]imidazol 2(3H)-one (44 mg, 0.3 mmol) and K2C0 3 (70 mg, 0.51 mmol) were poured into DMF (0.45 mL) and the resulting mixture was heated at 50'C overnight. The mixture was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as fluent) to afford 40 mg of 1-methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-lH benzo[djimidazol-2(3H)-one as a yellow oil (Yield: 43%). LCMS (RT) : 3.29min; MS (ES+) gave m/z : 292 1 H-NMR (CDC1 3 ), 5 (ppm) : 8.55-8.54 (d, 1H), 7.63-7.60 (m, 1H), 7.37-7.35 (d, 1H), 7.21-7.18 (m, 1H), 7.12-7.07 (m, 3H), 6.97-6.95 (m, 1H), 4.07-4.04 (t, 2H), 3.41 (s, 3H), 2.54-2.51 (t, 2H), 2.13-2.07 (m, 2H). Example 222 2-(4-(4,5-Dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d]F1,2,3]triazole 222(A) 2-Bromo-4,5-dimethylthiazole Bromine (272 [tL, 5.30 mnnol) was added dropwise to a solution of 4,5 dimethylthiazole (200 mg, 1.77 mmol) in chloroform (5 mL) at 0 0 C and the reaction mixture was stirred for 5 hours at room temperature. Sodium thiosulfate solution was WO 2005/123703 PCT/IB2005/002390 217 added to the reaction mixture and the aqueous phase was extracted with DCM. The organic phase was washed with water, brine, dried over Na 2
SO
4 , filtered and concentrated. The crude residue was purified by flash chromatography (pentane/Et 2 O 95:5) to yield 250mg (1.30 mmol, 74%) of 2-bromo-4,5-dimethylthiazole. 222(B) 2-(4-(4,5-Dimethylthiazol-2-vl)but-3-yny1)-2H-benzofd[l,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-4,5-dimethylthiazole (100 mg, 0.52 mmol) and 2-(but-3-yny1)-2H benzo[d][1,2,3]triazole (89 mg, 0.52 mmol, Example 109(D)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 25 mg (89 pimol, 17%) of 2-(4-(4,5-dimethylthiazol-2-yl)but-3-yny)-2H-benzo[d][1,2,3]triazole as a yellow solid (M.P. = 96-98'C). LCMS (RT) : 4.50min; MS (ES+) gave m/z : 283.1 Rf (cyclohexane/AcOEt 7:3) = 0.3. 'H-NMIR (CDC1 3 ), 6 (ppm) : 2.31 (s, 3H), 2.34 (s, 3H), 3.29 (t, J=7.5, 2H), 4.96 (t, J=7.5, 2H), 7.39 (dd, J=3.0 and 6.3, 2H), 7.86 (dd, J=3.0 and 6.3, 2H). Example 223 6-Fluoro-2-(4-(6-(fluoromethvl)pyridin-2-v1)but-3-ynv1)H-imidazo l,2-alpyridine 223(A) Trimethyl(4-(oxiran-2-vl)but-l-vnvl)silane To a stirred solution of trimethyl(prop-l-ynyl)silane (3 g, 26.7 mmol) in dry THF (100 mL) cooled at -72'C, was added drop by drop 2.5 N nBuLi in hexane solution (10.5 mL, 26.2 mmol). The resulting mixture was stirred at -75'C for 1h30. Then 2 (chloromethyl)oxirane (2.42 g, 26.2 mmol) in dry THF (2 mL) was slowly added. The resulting mixture was stirred at -72'C for 1h30, then warmed up to room temperature for an additional lh. The reaction mixture was quenched with water and extracted with diethyl ether. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford 4.50 g trimethyl(4-(oxiran-2-yl)but-1 ynyl)silane (Yield : 100%) as-a yellow oil which was used in the next step without further purification. Rf (Cyclohenaxe/AcOEt: 70/30)= 0.61 223 (B) 1-Bromo-6-(trimethylsilL)hex-5-yn-2-ol To a stirred solution of trimethyl(4-(oxiran-2-yl)but-1-ynyl)silane (4.5 g, 27 mmol) in THF (90 mL) containing acetic acid (4.81 g, 80.21 mmol), was added at 0 0 C anydrous LiBr (3.71 g, 42.78 mmol). The reaction mixture was left stirring overnight at room temperature. The reaction was quenched with saturated NaC1 and extracted with Et 2 O. The organic phase was washed once with a solution of 1M K 2 C0 3 saturated with NaCl, brine, dried over MgSO 4 , filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, from Cyclohxane 100% to DCM 100% as eluent) to afford 2.5 g of 1-bromo-6 (trimethylsilyl)hex-5-yn-2-ol (Yield: 38%) as a yellow oil. 'H-NMR (CDC1 3 ), 5 (ppm) : 3.95-3.80 (in, 1H), 3.65-3.30 (m, 2H), 2.38-2.20 (m, 3H), 1.75-1.65 (m, 2H), 0.05 (s, 9H) 223(C) 1-Bromo-6-(trimethylsily)hex-5-yn-2-one 1-bromo-6-(trimethylsilyl)hex-5-yn-2-ol (2.85 g, 10 mmol) were dissolved in acetone (13 mL).
WO 2005/123703 PCT/IB2005/002390 218 Preparation of Jone's reagent: 1.2 gr of Cr0 3 are dissolved in conc. H 2
SO
4 (1.2 mL). 5 mL of H 2 0 were added. The resulting mixture was stirred 10min until Cr0 3 was completely dissolved to give a red orange solution. The Jone's reagent was slowly added to the solution of 1-bromo-6-(trimethylsilyl)hex 5-yn-2-ol in acetone; the color gets green, green-brown then dark brown. Jone's reagent was added until the dark brown color remains. The reaction was monitored by TLC (DCM 100%), Rf=0.75 Isopropanol was added to quench the excess of Jone's reagent, and the product was extracted with DCM. The organic phases were washed twice with water, dried over MgS04, filtered and concentrated under reduced pressure to afford 1.85 g which was a mixture of 1-chloro-6-(trimethylsilyl)hex-5-yn-2-one and 1-bromo-6 (trimethylsilyl)hex-5-yn-2-one (in 1/1 ratio) as a yellow oil (Yield : 75%). The product was immediately used in next step without further purification. Rf (DCM: 100%)= 0.75 1 H-NMR (CDC1 3 ), 5 (ppm) mixture of a-chloroketone/a-bromoketone 1/1 ratio-: 4.04 (s, 2H, a-chloroketone), 3.84 (s, 2H, a-bromoketone), 2.90-2.70 (in, 2H, a chloroketone+ a-bromoketone), 2.50-2.40 (t, a-chloroketone+ a-bromoketone), 0.03 (s, 9H, a-chloroketone+ a-bromoketone). 223(D) 6-Fluoro-2-(4-(trimethylsilyl)but-3-vny1-imidazol.2-alpyridine To a stirred solution of 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (2.50 g, 10.11 mmol) in EtOH (8 mL) was added potassium carbonate (350 mg, 2.53 mmol) and 5 fluoropyridin-2-amine (567 mg, 5.06 mmol). The mixture was heated at 80'C overnight. The mixture was concentrated, the residue was dissolved in EtOAc, and the organic layer was washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, from DCM/MeOH : 100/0 to 96/4 as eluent) to afford 400 mg of 6-fluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 30%) as an orange-brown solid. Rf (DCM/MeOH: 95/5) = 0.38 LCMS (RT) : 3.05min; MS (ES+) gave m/z : 261 223(E) 2-(But-3-ynvl)-6-fluoro-imidazo 1,2-alpyridine According to the protocol described in Example 38(D), the conversion of 6-fluoro-2 (4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (400 mg, 1.53 mmol) afforded 220 mg of 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (Yield : 76%) as yellow oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: 98/2 as eluent). LCMS (RT) : 0.63-1.61min; MS (ES+) gave m/z: 189 Rf (DCM/MeOH: 95/5) =0.37 223(F) 6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-ylbut-3-vnyl)-imidazo[1,2 alpyridine The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (220 mg, 1.10 mol) and 2-(but-3 ynyl)-6-fluoro-imidazo[1,2-a]pyridine (220 mg, 1.14 mmol). The crude residue was purified over C18 chromatography (prepacked 35 g silicagel column, H 2 0/CH 3 CN : from 95/5 to 55/45 as eluent) to afford 155 mg of 6-fluoro-2-(4-(6- WO 2005/123703 PCT/IB2005/002390 219 (fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine (Yield : 46%) as a white powder (Mp = 140-141.8'C). LCMS (RT): 2.49min; MS (ES+) gave m/z: 298 Rf (DCM/MeOH : 95/5) =0.32 'H-NMR (CDC1 3 ), 6 (ppm): 8.65-8.60 (m, 1H), 7.80-7.70 (m, 2H), 7.50-7.40 (m, 1H, 7.38-7.30 (m, 1K), 7.25-7.10 (m, 1H), 5.41-2.25 (d, 2H), 2.93-2.88 (m, 2H), 2.80-2.75 (m, 2H). Example 224 6-Fluoro-2-(4-(2-(fluoromethv1)thiazol-4-vl)but-3-vn1)-imidazo[l,2-alpyridine 224(A) 4-Bromothiazole-2-carbaldehyde To a solution of 2,4-dibromothiazole (730 mg, 3.0 mmol) in anhydrous Et 2 O (15 mL) was added at -78'C, nBuLi 2.5M in hexane (1.4 mL, 3.6 mmol), and the resulting solution was stirred at the same temperature for 30 min. DMF (0.46 mL, 6 mmol) was added at -78'C and, after being stirred at -78'C for 30 min, the reaction mixture was slowly warmed up to room temperature over a period of 2h. Cyclohexane was added and the resulting mixture was passed through a short silica gel cake eluting with Cyclohexane/AcOEt 70/30 to give the 462 mg of 4-bromothiazole-2-carbaldehyde (Yield: 80%) which was used directly in the next step. 224(B) (4-Bromothiazol-2-y)methanol To a solution of 4-bromothiazole-2-carbaldehyde (462 mg, 2.40 mmol) in methanol (24 mL) was added at room temperature sodium borohydride (140 mg, 3.60 mmol), and the resulting mixture was stirred 1h at the same temperature. EtOAc (3 mL) and cyclohexane (6 mL) were added, and the mixture was passed through a short silica gel cake and eluting with EtOAc 100% to give 390 mg of (4-bromothiazol-2-yl)methanol (Yield: 83%) as a beige oil which slowly cristalize. LCMS (RT) : 2.43min; MS (ES+) gave m/z: 194 224(C) 4-Bromo-2-(fluoromethvl)thiazole A solution of (4-bromothiazol-2-yl)methanol (390 mg, 2.0 mmol) in 7 mL of dry DCM, was added dropwise -78'C to a solution at of DAST (0.738 mL, 6.0 mmol) in dry DCM (5.5 mL). The reaction mixture was stirred lh at -781C then lh at room temperature. The reaction was quenched with water, and the organic layer extracted with DCM, dried over MgS04, filtrated and evaporated. The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 95/5 as eluent) to afford 84 mg of 4-bromo-2 (fluoromethyl)thiazole as a yellow oil (Yield : 21%). LCMS (RT) : 3.3 8min; MS (ES+) gave m/z : 197 224(D) 6-Fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3 -vnv)-imidazo[1,2 alpyridine The title compound was prepared in accordance with the general method of Example 190(F), from 4-bromo-2-(fluoromethyl)thiazole (84 mg, 0.43 mmol) and 2-(but-3 ynyl)-6-fluoro-imidazo[1,2-a]pyridine (compound 223(E), 80 mg, 0.43 mmol). The crude residue was purified over C18 chromatography (prepacked 35 g silicagel column, H 2 0/CH 3 CN : from 100/0 to 80/20 as eluent) to afford 65 mg of 6-fluoro-2- WO 2005/123703 PCT/IB2005/002390 220 (4-(2-(fluoromethyl)thiazol-4-yl)but-3 -ynyl)-imidazo[1 ,2-a]pyridine (Yield : 47%) as a beige powder (Mp = 82-84'C). LCMS (RT) : 2.54min; MS (ES+) gave m/z : 304 Rf (DCM/MeOH : 95/5) =0.32 'H-NMR (CDC1 3 ), 6 (ppm) : 8.06-8.01 (t, 1H), 7.72-7.65 (m, 1H), 7.62-7.44 (m, 2H), 7.16-7.10 (t, 111), 5.64-5.54 (d, 2H), 3.15-3.12 (t, 2H), 2.92-2.89 (t, 2H) Example 225 8-Bromo-2-(4-(6-(fluoromethyl)pyridin-2-1)but-3-ynyl)-imidazo[1,2-alpyridine 225(A) 8-Bromo-2-(4-(trimethylsilyl)but-3-vny)-imidazo[l,2-alpyridine The title compound was prepared in accordance with the general method of Example 223(D), from 3-bromopyridin-2-amine (280 mg, 1.60 mmol) and 1-bromo-6 (trimethylsilyl)hex-5-yn-2-one (compound 223(C), 870 mg, 3.5 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH : from 100/0 to 98/2 as eluent) to afford 315 mg of 8-bromo-2-(4 (trimethylsilyl)but-3 -ynyl)-imidazo [1,2-a]pyridine (Yield : 61%) as a yellow oil. 225(B) 8-Bromo-2-(but-3-vnvl)-imidazo[ 1,2-alpyridine According to the protocol described in Example 38(D), the conversion of 8-bromo-2 (4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (315 mg, 0.98 mmol) afforded 241 mg of 8-bromo-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 98%) as yellow oil. LCMS (RT) : 0.76min; MS (ES+) gave m/z : 250 225(C) 8-Bromo-2-(4-(6-(fluoromethvl)pyridin-2-yl)but-3-vnvl)H-imidazo[1,2 alpyridine The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (180 ing, 0.97 mmol) and 8-bromo-2 (but-3-ynyl)-imidazo[1,2-a]pyridine (242 mg, 0.97 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel colunin, Cyclohexane/AcOEt : from 100/0 to 60/40 as eluent) to afford 36 mug of 8-bromo-2 (4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 10%) as a yellow oil. LCMS (RT) : 2.58min; MS (ES+) gave m/z: 358 'H-NMR (CDC1 3 ), 6 (ppm) : 8.08-8.04 (d, 111), 7.73-7.67 (t, lH), 7.62 (s, 1H), 7.45 7.41 (d, 1H), 7.41-7.37 (d, 1H), 7.34-7.31 (d, 1H), 6.67-6.62 (t, 1H), 3.15-3.25 (t, 2H), 3.00-2.90 (t, 2H) Example 226 8-(Benzvloxv)-2-(4-(6-(fluoromethv)pridin-2-vlbut-3-vnv1)-imidazo[l,2-alpyridine 226(A) 8-(Benzyloxy)-2-(4-(trimethylsilyl)but-3-ynl)-imidazo[1,2-alpyridine The title compound was prepared in accordance with the general method of Example 223(D), from 3-(benzyloxy)pyridin-2-amine (274 mg, 1.37 mmol) and 1-bromo-6 (trimethylsilyl)hex-5-yn-2-one (compound 223(C), 750 mg, 3.0 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, WO 2005/123703 PCT/IB2005/002390 221 DCM/MeOH : from 98/2 to 95/5 as fluent) to afford 331 mg of 8-(benzyloxy)-2-(4 (trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine (Yield: 69%) as a yellow oil. LCMS (RT) : 3.68min; MS (ES+) gave m/z: 349 226(B) 8-(Benzyloxy)-2-(but-3-ynvl)-imidazorl,2-alpyridine According to the protocol described in Example 38(D), the conversion of 8-bromo-2 (4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (331 mg, 0.95 mmol) afforded 183 mg of 8-(benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 70%) as yellow-oil. LCMS (RT) : 2.5 8min; MS (ES+) gave m/z : 277 226(C) 8-(Benzyloxv)-2-(4-(6-(fluoromethyl)ridin-2-vl)but-3-ynv1)H-imidazo[1,2 alpydine The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (82 mg, 0.43 mmol) and 8 (benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (119 mg, 0.43 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : from 100/0 to 60/40 as eluent) to afford 10 mg of 8 (benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-alpyridine (Yield: 6%) beige solid (Mp = 92-94'C) LCMS (RT) : 3.01min; MS (ES+) gave m/z: 386 'H-NMR (CDCl 3 ), 5 (ppm) : 7.75-7.65 (in, 2H), 7.55-7.30 (in, 8H), 6.60-6.50 (t, 1H), 6.45-6.35 (d, 1H), 5.55-5.40 (d, 2H), 5.35 (s, 2H), 3.19-3.14 (t, 2H), 2.96-2.91 (t, 2H) Example 227 2-(4-(6-(Fluoromethvl)pyridin-2-yl)bnt-3-ynvl)-8-phenl-imidazof1,2-alpvridine To a solution of 8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2 a]pyridine (compound 171(C), 301 mg, 0.84 mmol) and phenylboronic acid (50 mg, 1.3 mmol) in degazed DME (4.2 mL) was added 1.32 mL of a solution of K 3 P0 4 2M (degazed before use). After stirring at room temperature for 5 min under N 2 , Pd(PPh 3
)
4 (190 mg, 0.17 mmol) was added in one portion. The resulting mixture was heated at 80'C for 4h. The Mixture was cooled down to room temperature and diluted in AcOEt. The organic layer was washed twice with saturated NaCl, dried over magnesium sulfate, filtered and concentrated. The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : 60/40 as eluent) to afford 137 rug of 2-(4-(6-(fluoromethy)pyridin-2-yl)but-3-ynyl) 8-phenyl-imidazo[1,2-a]pyridine (Yield : 46%) as a yellow oil. LCMS (RT) : 3.19min; MS (ES+) gave m/z: 356 'H-NMR (CDC1 3 ), a (ppm) : 8.80-8.40 (d, 1H), 8.40-8.00 (in, 2H), 7.72-7.66 (t, 1H), 7.57 (s, 1H), 7.51-7.23 (in, 6H), 6.87-6.81 (t, 1H), 5.52-5.41 (d, 2H), 3.19-3.16 (t, 2H), 2.96-2.93 (t, 2H) Example 228 6,8-Difluoro-2-(4-(pyridin-2-yl)but-3-ynl)-imidazo[1,2-alpyridine WO 2005/123703 PCT/IB2005/002390 222 228(A) 6,8-Difluoro-2-(4-(trimethylsilvl)but-3-vny1)-inidazo[1,2-alpyridine The title compound was prepared in accordance with the general method of Example 223(D), from 3,5-difluoropyridin-2-amine (492 mg, 3.78 nnol) and 1-bromo-6 (trimethylsilyl)hex-5-yn-2-one (compound 223(C), 1.87 mg, 7.56 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, from DCM/Cyclohexane: 70/30 to DCM/MeOH : 95/5 as eluent) to afford 517 mg of 6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 49%) as a brown oil. LCMS (RT) : 4.43min; MS (ES+) gave m/z : 279 'H-NMR (CDC1 3 ), 6 (ppm) : 7.80 (s, 1H), 7.45 (d, 1H), 7.81-7.72 (t, 1H), 3.00-2.90 (t, 2H), 2.65-2.50 (t, 2H), 0.05 (s, 9H) 228(B) 2-(But-3-vnl)-6,8-difluoro-imidazo[l,2-alpyridine According to the protocol described in Example 38(D), the conversion of 6,8 difluoro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (517 mg, 1.86 mmol) afforded 363 mg of 2-(but-3-ynyl)-6,8-difluoro-imidazo[1,2-a]pyridine (Yield : 95%) as yellow-oil. LCMS (RT) : 2.55min; MS (ES+) gave m/z : 207 1 H-NMR (CDC1 3 ), S (ppm) : 7.80 (s, 1H), 7.50 (s, 1H), 6.84-6.70 (t, 1H), 3.00-2.90 (t, 2H), 2.65-2.50 (t, 2H), 1.90 (s, 1H) 228(C) 6,8-Difluoro-2-(4-(pyridin-2-vl)but-3-ynvl)-imidazo[1,2-alpyridine In a dry flask were added Cul (16.9 mg, 0.08 mmol) and TEA (5 mL) followed by 2 iodopyridine (363 mg, 1.77 mmol) and Pd(PPh 3
)
2
C
2 (82 mg, 0.088 mmol). A yellow suspension was obtained after 5min of stirring. To this suspension was added 2-(but 3-ynyl)-6,8-difluoro-iniidazo[1,2-a]pyridine (365 mg, 1.77 mmol) and the reaction mixture turns to black. After 4h at room temperature, the TEA was evaporated; the crude product was dissolved in DCM and filtered over celite. The organic layer was washed with aqueous 2N ammonia, brine, dried over MgS04, and the solvent was evaporated to give a brown solid (588 mg). The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/AcOEt: form 100/0 to 95/5 as eluent) to afford 293 mg of 6,8-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl) imidazo[1,2-a]pyridine. A second purification over C18 was performed using
H
2 0/CH 3 CN : from 80/20 to 70/30 as eluent) to afford 146 mg of the title compound as a brownish powder contaminated by PPh 3 O. The solid was dissolved in aqueous 0.1N HC1 (20 mL)1 and the aqueous phase was washed twice with DCM (3*10 mL). The aqueous layer was neutralised with sat NaHCO 3 and extracted in ether (3*10 mL). The organic layer was washed with water (10 mL), brine (10 mL), and dried over MgSO 4 . Evaporation of the solvent afford 124 mg of 6,8-difluoro-2-(4-(pyridin 2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield : 25%) as a white solid (Mp = 130 131 C). LCMS (RT) : 2.67min; MS (ES+) gave m/z: 284 Rf (DCM/MeOH: 96/4) =0.23 1 H-NMR (CDC1 3 ), S (ppm) : 8.50-8.40 (d, 1H), 7.90-7.80 (m, 1H), 7.60-7.50 (m, 2H), 7.35-7.25 (d, 1H), 7.18-7.08 (m, 1H), 6.86-6.72 (t, 1H), 3.15-3.00 (t, 2H), 2.90-2.80 (t, 2H) WO 2005/123703 PCT/IB2005/002390 223 Example 229 2-(4-(4-Methylthiazol-2-yllbut-3-yny1)-2H-benzod] [1,2,3]triazole 229(A) 2-Bromo-4-methylthiazole A solution of sodium nitrite (378 mg, 5.47 mmol) in water (2.25 mL) was added to a mixture of 4-methyl-thiazol-2-ylamine (500 mg, 4.38 mmol), phosphoric acid (4.50 mL) and nitric acid (2.25 mL) at -10 C. After stirring the reaction mixture for 45 min. at -10'C, it was poured onto a solution of CuSO 4 (1.37 g, 5.47 mmol) and sodium bromide (1.13 g, 10.9 mmol). Then the solution was stirred for 30 min. at room temperature, for 3 hours at 50'C and was neutralized with a solution of NaOH (2M). The aqueous phase was extracted with DCM. The organic phase was washed with water, brine, dried over Na 2
SO
4 , filtered and concentrated. The crude residue was purified by flash chromatography (pentane/ether 95:5) to yield 250 mg (1.40 mmol, 32%) of 2-bromo-4-methylthiazole as an orange oil. LCMS (RT) : 3.62min; MS (ES+) gave m/z: 179.1. 229(B) 2-(4-(4-Methylthiazol-2-yl)but-3-yny)-2H-benzo[d[1,2,31triazole The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-4-methylthiazole (100 mg, 0.56 mmol) and 2-(but-3-ynyl)-2H benzo[d][1,2,3]triazole (96 mg, 0.56 mmol, Example 109(D)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 40 mg (0.15mmol, 27%) of 2-(4-(4-methylthiazol-2-yl)but-3-ynyl)-2H benzo[d][1,2,3]triazole as a white solid (M.P. = 78-80'C). LCMS (RT) : 4.05min; MS (ES+) gave m/z : 269.1 Rf (cyclohexane/AcOEt 7:3) = 0.3. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.44 (s, 3H), 3.31 (t, J=7.5, 2H), 4.98 (t, J=7.5, 2H), 6.85 (s, 1H), 7.39 (dd, J=3.3 and 6.3, 2H), 7.87 (dd, J=3.3 and 6.3, 2H). Example 230 (3-Fluoropyridin-2-yl)but-3-ynyl)benzordloxazole 230(A)3-Fluoro-2-iodopyridine To a solution of 2-chloro-3-fluoropyridine (400 mg, 3 mmol) in dioxane (6 mL, 0.5M) was added in one portion chlorotrimethylsilane (652 mg, 6 mmol) and sodium iodide (2.20 g, 15 mmol). The resulting mixture was stirred at 80'C overnight. The reaction mixture was concentrated to afford 660 mg of 3-fluoro-2-iodopyridine (Yield : 98%) as a yellow oil which was used in the next step without further purification. 230(B) (3-Fluoropyridin-2-vl)but-3-ynyl)benzo[dloxazole In a dry reaction tube containing in suspension copper iodide (28 mg, 0.148 mol) and triethylamine (8.30 mL, 59.20 mmol), were added 3-fluoro-2-iodopyridine (660 mg, 2.96 mmol) and Pd(PPh 3
)
2 Cl 2 (104 mg, 0.148 mmol) under N 2 . A yellow suspension was obtained. After a 5 minutes of stirring at room temperature, was added a solution 2-(But-3-ynyl)benzo[d]oxazole (compound 8(A), 510 mg, 3 mmol) in triethylamine (0.2 mL) under N 2 . Immediatly the color of the reaction turns to black. The mixture was stirred at room temperature for 30min and heated at 50'C overnight under N 2 . Triethylamine was removed under reduce pressure and the crude product was purified by flash chromatography (Prepacked column 50 g, Cyclohexane/AcOEt : 60/40 as WO 2005/123703 PCT/IB2005/002390 224 eluent) following by C18 chromatography (Prepacked column 15 g, H 2 0/CH 3 CN from 80/20 to 40/600 as eluent) to afford 120 mg of 2-(4-(3-fluoropyridin-2-yl)but-3 ynyl)benzo[d]oxazole(Yield: 15%) as white powder (Mp = 86-88'C). LCMS (RT): 4.06min; MS (ES+) gave m/z: 267 'H-NMR (CDC1 3 ), 6 (ppm) : 8.39-8.36 (m, 1H), 7.73-7.68 (m, 1H), 7.53-7.49 (in, 1H); 7.42-7.38 (m, 1H), 7.35-7.30 (m, 2H), 7.27-7.22 (m, 111), 3.35-3.32 (t, 2H), 3.15 3.12 (t, 2H) Example 231 2-(4-(2-Methyl-1H-imidazol-4-y1)but-3-ynv1)benzolidloxazole 231(A)Ethyl 4-iodo-2-methyl-1H-imidazole-1-carboxylate To a solution of 4-iodo-2-methyl-1H-imidazole (162 mg, 0.78 mmol) in THF (2.6 mL, 0.3M) containing DIEA (0.33 mL, 1.95 mmol) and DMAP (47 mg, 0.039 mmol), cooled in a ice bath at 0 0 C, was added a solution of Ethyl chloroformate (211 mg, 1.95 mmol) in THF (2 mL, 1M). The reaction mixture was heated at 50'C for 48h and then concentrated. The residue was dissolved in DCM and the organic layer was washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (Prepacked column 10 g, DCM/MeOH : 97/3 as fluent) to afford 208 mg of ethyl 4-iodo-2-methyl-1H imidazole-1-carboxylate (95%) as colorless oil. LCMS (RT) : 3.69min; MS (ES+) gave m/z: 281 231(B) Ethyl 4-(4-(benzo[dloxazol-2-Y)but-1-vnyv1-2-methyl-1H-imidazole-1 carboxylate According to the general protocol for Sonogashira coupling described in Example 38(E), the conversion of ethyl 4-iodo-2-methyl-1H-imidazole-l-carboxylate (686 mg, 2.45 mmol) afforded 369 mg of ethyl 4-(4-(benzo[d]oxazol-2-yl)but-1-ynyl)-2 methyl-1H-imidazole-l-carboxylate (Yield: 46%) as a beige powder. The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 50/50 as eluent) LCMS (RT) : 4.18min; MS (ES+) gave m/z : 324 Rf (Cyclohexane/AcOEt: 50/50) =0.35 231(C) 2-(4-(2-Methyl-1H-imidazol-4-yl)but-3-ynvl)benzofdloxazole A solution 2.0 N of NaOH was added dropwise to a solution of ethyl 4-(4 (benzo[d]oxazol-2-yl)but-1-ynyl)-2-methyl-1H-iinidazole-1-carboxylate (369 mg, 1.14 mmol) in EtOH (5.7 mL) and the mixture was heated at 80 C overnight. Ethanol was concentrated under reduce pressure, then water was added and the aqueous layer was extracted with DCM. The recombined organics layers were washed once with saturated NaCl, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH : 97/3 as eluent) to afford 102 mg of 2-(4-(2-methyl 1H-imidazol-4-yl)but-3-yny)benzo[d]oxazole (Yield: 35%) as a beige powder (Mp 152-154-C). LCMS (RT) : 2.46min; MS (ES+).gave m/z : 252 Rf (DCM/MeOH: 95/5) =0.4 'H-NMR (CDC1 3 ), 8 (ppm) : 7.70-7.67 (m, 1H), 7.52-7.48 (m, 1H), 7.34-7.27 (m, 2H), 7.03 (s, 1H), 3.25-3.22 (t, 2H), 3.03-3.00 (t, 2H), 2.38 (s, 3H) WO 2005/123703 PCT/IB2005/002390 225 Example 232 5-(6-(Fluoromethyl)pyrdin-2-v1)-N-(4-fluorophenv1)pent-4-ynamide 232(A) (4-Fluoro-phenyl)-pent-4-ynovl-carbamic acid tert-butvl ester The title compound was prepared in accordance with the general method of Example 34(B), from N-(4-fluorophenyl)pent-4-ynamide (400 mg, 2.09 mmol, 34(A)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 505 mg (1.73 mmol, 83%) of (4-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester as a colorless oil. LCMS (RT) : 4.72min; MS (ES+) gave m/z : 192.1. 232(B) [5-( 6 -Fluoromethyl-pyridin-2-yl)-pent-4-ynov11-(4-fluoro-phenvl)-carbamic acid tert-butyl ester The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.95 mmol, Example 190(E)) and (4-fluoro-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester (276 mg, 0.95 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 300 mg (0.75 mmol, 79%) of [5-(6-fluoromethyl pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamic acid tert-butyl ester as a white solid. LCMS (RT) : 4.90min; MS (ES+) gave m/z : 301.1. Rf (cyclohexane/AcOEt 4:1) = 0.2. 232(C) 5-(6-(Fluoromethv1)pyridin-2-vl)-N-(4-fluoropheny1)pent-4-ynamide The title compound was prepared in accordance with the general method of Example 34(D), from [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl) carbamic acid tert-butyl ester (300 mg, 0.75 mmol). After the work-up, the crude residue was washed with diisopropyl ether to yield 120 mg (0.40 mmol, 53%) of 5-(6 (fluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)pent-4-ynamide as a beige powder (M.P. = 110 C). LCMS (RT) : 3.77min; MS (ES+) gave m/z : 301.1. 1 H-NMR (CDC1 3 ), 5 (ppm) : 2.68 (t, J=6.9, 2H), 2.88 (t, J=6.9, 2H), 5.46 (d, J=46.8, 2H), 6.95-7.04 (2H), 7.32 (d, J=8.1,1H), 7.40 (d, J=7.5, 1H), 7.43-7.52 (311), 7.67 7.74 (m, 1H). Example 233 2-(4-(1,2-Dimethyl-lH-imidazol-4-yl)but-3-nyl)benzordloxazole In a dry microwave tube were placed in suspension CuI (19 mg, 0.1 mmol) and triethylamine (3.79 mL, 27 mmol). Then under nitrogen atmosphere, were added the 4-bromo-1,2-dimethyl-1H-i-midazole (350 mg, 2.0 mmol), PdC1 2 (PPh 3
)
2 (70 mg, 0.1 mmol) , and triphenyl phosphine polymerbound (130 mg, 0.4 mmol). The suspension was stirred at room temperature for few minutes, finally the 2-(But-3 ynyl)benzo[d]oxazole (compound 43(A), 340 mg, 2.0 mmol) in 0.4 mL of DMF was added, and the reaction mixture is stirred at room temperature for 30 min. The reaction mixture was stirred and heated under micro wave irradiation for 25 min at 120'C. After filtering to remove triphenyl phosphine polymerbound., the triethylamine was concentrated under reduce pressure and the residue was dissolved WO 2005/123703 PCT/IB2005/002390 226 in DCM. The organic layer was washed with saturated NaHCO 3 , H20 and brine. The organic layer was dried over Na 2
SO
4 , filtered and concentrated. Purification over C18 chromatography (prepacked 35 g C18 column, H 2 0/CH 3 CN: from 100/0 to 60/40 as eluent) to afford 28 mg of 2-(4-(1,2-dimethyl-lH-imidazol-4 yl)but-3-ynyl)benzo[d]oxazole (Yield: 5%) as a beige powder (Mp = 117-119 0 C). LCMS (RT) : 2.53min; MS (ES+) gave m/z: 266 'H-NMR (CDC1 3 ), S (ppm) :7.69-7.67 (m, 1H), 7.50-7.48 (in, 1H), 7.32-7.27 (m, 2H), 6.89 (s, 1H), 3.54 (s, 3H), 3.28-3.22 (t, 2H), 3.04-2.98 (t, 2H), 2.36 (s, 3H) Example 234 2-(4-(Pyridin-2-v1)but-3-vnyl)isoindolin-1-one 234(A) Methyl-2-(bromomethyl)benzoate A solution of methyl-2-methylbenzoate (250 mg, 1.66 mmol), NBS (296 mg, 1.66 mmol) and dibenzoylperoxide (403 mg, 1.66 mmol) was stirred under reflux for one day. After purification by flash chromatography, 350 ing (1.53 mmol, 92%) of methyl-2-(bromomethyl)benzoate were obtained as a colorless oil. 234(B) 2-(4-(Trimethylsilyllbut-3-vnyl)isoindolin-l-one 4-Trimethylsilyl)but-3-yn-1-amine (215 mg, 1.52 mmol), methyl-2 (bromomethyl)benzoate (349 mg, 1.52 mmol) and Et 3 N (0.42 mL, 3.04 mmol) were placed in a microwave tube and heated for 10 min. at 100'C. The solvent was evaporated and the crude residue was dissolved in DCM. The organic phase was washed with water, brine, dried over Na 2
SO
4 , filtered and concentrated to yield 250 mg (0.97 mmol, 64%) of 2-(4-(trimethylsilyl)but-3-ynyl)isoindolin-1-one as a colourless oil. 234(C) 2-(But-3-vnyl)isoindolin-l -one The title compound was prepared in accordance with the general method of Example 108(B), from 2-(4-(trimethylsilyl)but-3-ynyl)isoindolin-1-one (250 mg, 0.97 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 85 mg (0.46 mmol, 47%) of 2-(but-3-ynyl)isoindolin-1-one as a colourless oil. LCMS (RT) : 3.03min; MS (ES+) gave m/z : 186.1. 234(D) 2-(4-(Pyridin-2-v1)but-3 -nvl)isoindolin- 1-one The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (94 mg, 0.46 mmol) and 2-(but-3-ynyl)isoindolin-l-one (85 mg, 0.46 mmol). Reaction conditions: 14 hours at room temperature. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1 to 0:1) to yield 45 mg (0.17 mmol, 37%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindolin-1-one as a white solid (M.P. = 94-98'C). LCMS (RT) : 2.90min; MS (ES+) gave m/z : 263.2. Rf (AcOEt) = 0.3. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.83 (t, J=6.6, 2H), 3.89 (t, J=6.6, 2H), 4.60 (d, J=6.6, 2H), 7.14-7.24 (m, 1H), 7.33 (d, J=7.8,1H), 7.40-7.55 (3H), 7.56-7.67 (m, 1H), 7.84 (d, J=6.9, 1H), 8.48-8.60 (in, 1H).
WO 2005/123703 PCT/IB2005/002390 227 Example 235 4-(Pyridin-2-vyl)but-3-ynyl 2-chlorobenzoate 235(A)4-(Pyridin-2-v1)but-3-yn-1-ol In a dry microwave tube were placed in suspension CuI (49.5 mg, 0.26 mmol) and triethylamine (9.85 mL, 70.20 mmol). Then under nitrogen atmosphere, were added the 2-bromopyridine (822 mg, 5.2 mmol), PdCl 2 (PPh 3
)
2 (182 mg, 0.26 mmol) , and triphenyl phosphine polymerbound (350 mg, 1.0 mmol). The suspension was stirred at room temperature for few minutes, finally the but-3-yn- 1 -ol (364 mg, 5.20 mmol) in 0.5 mL of DMF was added, and the reaction mixture is stirred at room temperature for 30 min. The reaction mixture was stirred and heated under micro wave irradiation for 1 0min at 120'C. After filtering to remove triphenyl phosphine polymerbound, the triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NaHCO 3 , H 2 0 and brine. The organic layer was dried over Na 2 S04, filtered and concentrated. Purification over silicagel chromatography (prepacked 50 g silicagel column, DCM/MeOH : 98/2 as eluent) to afford 620 mg of 4-(pyridin-2-yl)but-3-yn-1-ol (Yield: 81%) as a yellow oil. LCMS (RT) : 1.76min ; MS (ES+) gave m/z : 148 235(B) 4-(Pyridin-2-yl)but-3-vny 2-chlorobenzoate To solution of 2-chlorobenzoic acid (330 mg, 2.10 mmol), 4-(pyridin-2-yl)but-3-yn-1 ol (310 mg, 2.1 mmol), in DCM (7 mL), was successively added EDCI.HC1 (600 mg, 3.2 mmol) and DMAP (13 mg, 0.105 mmol). The resulting mixture was then stirred overnight at ambient temperature.The reaction mixture was concentrated. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : 80/20 as fluent) to afford 260 mg of 4-(pyridin-2-yl)but-3-ynyl 2-chlorobenzoate (Yield : 43%) as a yellow oil. Rf (Cyclohexane/AcOEt: 80/20) = 0.30 LCMS (RT) : 4.19min ; MS (ES+) gave m/z : 286 1 H-NMR.(CDC1 3 ), 6 (ppm) :8.55 (s, 1H), 8.06 (s, 1H), 7.98-7.95 (d, 1H), 7.67-7.61 (t, 1H), 7.56-7.52 (d, 1H), 7.42-7.37 (m, 2W), 7.24-7.18 (m, 1H), 4.55-4.52 (t, 2H), 2.95 2.93 (t, 2H) Example 236 4-(Pyridin-2-yl)but-3-Ynvl 3-chlorobenzoate According to the protocol described in Example 235(B), the conversion of 3 chlorobenzoic acid (330 mg, 2.10 mmol) afforded 350 mg of 4-(pyridin-2-yl)but-3 ynyl 3-chlorobenzoate (Yield: 58%) as yellow-oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 80/20 as eluent) Rf (Cyclohexane/AcOEt: 80/20) = 0.30 LCMS (RT) : 4.53min; MS (ES+) gave m/z : 286 1 H-NMR (CDCl 3 ), 8 (ppm) : 8.58-8.55 (d, 1H), 7.91-7.87 (d, 1H), 7.66-7.60 (t, 1H), 7.48-7.38 (m, 3H), 7.35-7.30 (t, 1H), 7.24-7.19 (m, 1H), 4.57-4.54 (t, 2H), 2.96-2.93 (t, 2H).
WO 2005/123703 PCT/IB2005/002390 228 Example 237 3-Chlorophenyl 5-(pyridin-2-y1)pent-4-ynoate 237(A) 3-Chlorophenyl pent-4-ynoate According to the protocol described in Example 235(B), the reaction between pent-4 ynoic acid (590 ng, 6.0 mmol) and 3-chlorophenol (771 mg, 6.0 mmol) afforded 1.19 g of 3-chlorophenyl pent-4-ynoate (Yield: 95%) as colorless-oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 90/10 as eluent) Rf (Cyclohexane/AcOEt : 90/10) = 0.30 LCMS (RT) : 4.68m in; MS (ES+) no MH+ detected 237(B) 3-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate In a dry microwave tube were placed in suspension Cul (26.7 mg, 0.14 mmol) and triethylamine (5.30 mL, 37.80 mmol). Then under nitrogen atmosphere, were added the 2-iodopyridine (574 mg, 2.80 mmol), PdCl 2 (PPh 3
)
2 (98 Mg, 0.14 mmol) , and triphenyl phosphine polymerbound (190 mg, 0.56 mmol). The suspension was stirred at room temperature for few minutes, finally the 3-chlorophenyl pent-4-ynoate (580 mg, 2.80 mmol) in 0.2 mL of DMF was added, and the reaction mixture is stirred at room temperature for 30 min. The reaction mixture was stirred and heated under micro wave irradiation for 8min at 120'C. After filtering to remove triphenyl phosphine polymerbound, the triethylamine was concentrated under reduce pressure, the residue was dissolved in DCM. The organic layer was washed with saturated NaHCO 3 , H20 and brine. The organic layer was dried over Na 2 S04, filtered and concentrated. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 80/20 as fluent) to afford 210 mg of 3-chlorophenyl 5-(pyridin 2-yl)pent-4-yno ate (Yield: 26%) as a yellow oil. Rf (Cyclohexane/AcOEt : 80/20) = 0.30 LCMS (RT) : 4.33min; MS (ES+) gave m/z : 286 'H-NMR (CDCl 3 ), S (ppm) : 8.59-8.56 (d, 111), 7.66-7.61 (t, 111), 7.42-7.38 (d, 1H), 7.34-7.17 (in, 411), 7.06-7.02 (d, 1H), 2.95-2.86 (in, 4H) Example 238 3-Chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate According to the protocol described in Example 237(B), the reaction between 3 chlorophenyl pent-4-ynoate (580 mg, 2.80 mmol) and 2-chloro-3-fluoropyridine (370 mg, 2.80 mmol) afforded Il 1 mg of 3-chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4 ynoate (Yield: 13%) as yellow-oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 80/20 as fluent) Rf (Cyclohexane/AcOEt: 80/20) = 0.32 LCMS (RT) : 4.6 1min ; MS (ES+) gave m/z : 304 'H-NMR (CDCl 3 ), S (ppm) : 8.42-8.38 (in, 111), 7.45-7.40 (t, 1H), 7.34-7.17 (in, 4H), 7.07-7.03 (in, 111), 2.95 (s, 4H) WO 2005/123703 PCT/IB2005/002390 229 Example 239 2-Chlorophenyl 5-(pyridin-2-y1)pent-4-ynoate 239(A)2-Chlorophenyl pent-4-ynoate According to the protocol described in Example 235(B), the reaction between pent-4 ynoic acid (590 mg, 6.0 mmol) and 2-chlorophenol (771 mg, 6.0 mmol) afforded 1.09 g of 2-chlorophenyl pent-4-ynoate (Yield: 87%) as colorless-oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 90/10 as eluent) Rf (Cyclohexane/AcOEt: 90/10) = 0.30 LCMS (RT) : 4.41min ; MS (ES+) no MH+ detected 239(B) 2-Chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate According to the protocol described in Example 237(B), the reaction between 2 chlorophenyl pent-4-ynoate (420 mg, 2.00 mmol) and 2-iodopyridine (410 mg, 2.00 mmol) afforded 208 mg of 2-chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate (Yield: 36%) as yellow-oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : form 90/10 to 80/20 as eluent) Rf (Cyclohexane/AcOEt: 80/20)= 0.32 LCMS (RT) : 4.21min ; MS (ES+) gave m/z : 286 'H-NMR (CDC1 3 ), 5 (ppm) : 8.59-8.55 (d, 1H), 7.66-7.61 (t, 1H), 7.47-7.43 (d, 1H), 7.42-7.38 (d, 1H), 7.32-7.26 (in, 1H), 7.24-7.16 (m, 3H), 3.03-2.98 (m, 2H), 2.96-2.90 (m, 2H) Example 240 2-Chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate 240(A) 4-Bromo-2-methylthiazole To a solution of 2,4-Dibromothiazole (1.00 g, 4.10 mmol) in anhydrous Et 2 O (14 mL) was added dropwise at -78'C, 2.1 mL of nBuLi 2.5M in hexane (5.30 mmol). The mixture was stirred for 2h at -78'C. Then a solution of methyl trifluoromethanesulfonate (673 mg, 4.10 mmol) in THF (2 mL) was added dropwise at -78'C, the resulting mixture was stirred 30min at -78'C. The reaction mixture was warmed slowly to room temperature. The reaction was cooled with an ice bath at 1 0 0 C and quenched with water. The two layers were separated; the aqueous layer was extracted with Ethylic ether. The combined organic layers were dried over Na 2
SO
4 , filtered and concentrated under medium pressure 700 mbar, bath 35'C, because the bromothiazole is very volatile. The product was purified by flash chromatogtraphy silice 40-60, pack 70 g, Pentane/Et 2 O : 95/5 as eluent to afford 420 mg of 4-bromo-2 methylthiazole (Yield: 57%) as a colorless oil. Rf (Pentane/Et 2 0: 95/5) = 0.32 LCMS (RT) : 3.29min ; MS (ES+) gave m/z: 179 240(B) 4-Iodo-2-methylthiazole To a solution of 4-bromo-2-methylthiazole (418 mg, 2.35 mmol) in anhydrous Et 2 O (3 mL) was added dropwise at -78'C, 0.14 mL of nBuLi 2.5M in hexane (2.80 mmol). The mixture was stirred for 1h at -78'C. Then a solution of diiodoethane (1.30 g, 4.70 WO 2005/123703 PCT/IB2005/002390 230 mmol) in 0.4 mL of Et 2 O was added dropwise at -78'C, and the resulting mixture was stirred 30min at -78'C. The reaction was then warmed slowly to room temperature over a period of 2h. The reaction was cooled with a ice bath at -10CC was quenched with water. The two layers were separated and the aqueous layer was extracted with Et 2 O. The combined organic layers were dried over Na 2 S 04, filtered and concentrated under medium pressure. Purification over silicagel chromatography (prepacked 10 g silicagel column, Pentane/Et 2 O: 95/5 as eluent) to afford 240 mg of 4-iodo-2-methylthiazole (Yield 45%) as a colorless oil. LCMS (RT) : 3.49min ; MS (ES+) gave m/z: 225 240(C) 2-Chlorophenvl 5-(2-methylthiazol-4-yl)pent-4-vnoate According to the protocol described in Example 237(B), the reaction between 2 chlorophenyl pent-4-ynoate (compound 160(A), 290 mg, 1.40 mmol) and 4-iodo-2 methylthiazole (315 mg, 1.40 mmol) afforded 145 mg of 2-chlorophenyl 5-(2 methylthiazol-4-yl)pent-4-ynoate (Yield: 34%) as yellow-oil. Purification over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : form 90/10 to 8 0/20 as eluent) Rf (Cyclohexane/AcOEt: 80/20) = 0.32 LCMS (RT) : 4.61imin ; MS (ES+) gave m/z : 306 IH-NMR (CDC1 3 ), 5 (ppm) : 7.47-7.43 (in, 1H), 7.32-7.26 (in, 1H), 7.23-7.15 (in, 3H), 3.00-2.95 (m, 2H), 2.92-2.87 (m, 2H) Example 241 2-(4-(6-(Fluoromethyl)pyridin-2-y)but-3-vnyl)benzordlthiazole The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (266 mg, 1.40 mmol) and 2-(but-3 ynyl)benzo[d]thiazole (compound 35(A), 260 mg, 1.40 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt : from 100/0 to 80/20 as eluent) to afford 160 mg of 2-(4-(6 (fluoromethyl)pyridin-2-yl)but-3-ynyl)benzo[d]thiazole (Yield : 38%) as a beige powder (Mp = 74-76'C). LCMS (RT) : 4.38min; MS (ES+) gave m/z : 297 Rf (Cyclohexane/AcOEt: 80/20) =0.30 'H-NMR (CDC1 3 ), 8 (ppm) : 8.03-7.99 (d, 1H), 7.89-7.85 (d, 1H), 7.73-7.67 (t, 1H), 7.51-7.45 (t, 1H), 7.42-7.32 (m, 311), 5.52-5.43 (d, 2H), 3.49-3.44 (t, 2H), 3.09-3.04 (t, 2H) Example 242 2-(5-(Pyridin-2-yl)pent-4-ynvllisoindoline-1,3-dione 242(A) 5-(Pyridin-2-yl)pent-4-yn-1-ol In a dry microwave tube were placed in suspension, CuI (57 mg, 0.30 mmol) and triethylamine (10.10 ml, 72 mmol). Then under nitrogen, were added the 2 bromopyridne (948 mg, 6.0 mmol), PdC1 2 (PPh 3
)
2 (211 mg, 0.30 mmol) and triphenyl phosphine polymerbound (310 mg, 1.20 mol). The suspension was stirred at room WO 2005/123703 PCT/IB2005/002390 231 temperature for 5 minutes, finally pent-4-yn-1-ol (500 mg, 6.0 mmol) in DMF (8.60 mL) was added, and the reaction mixture was stirred at room temperature for 3 0min. The reaction mixture was stirred and heated with micro wave for 20 min at 120 C. Triethylamine was concentrated under reduce pressure; the residue was dissolved in DCM. The organic layer was washed with NaHCO 3 , H20 and saturated brine. The organic layer was dried over Na 2
SO
4 , filtered and concentrated. Purification by flash chromatography pack 50g, silice 40-60, DCM/AcOEt : from 100/0 to 50/50 as fluent to afford 702 mg of 5-(pyridin-2-y1)pent- 4 -yn-1-ol (Yield: 72%) as a colorless oil. LCMS (RT) : 1.94min; MS (ES+) gave m/z: 162 Rf (DCM/AcOEt: 50/50) =0.30 242(B) 2-(5-Bromopent-1-vny1)pyridine Bromine (3.45 g, 21.4 mmol) was added to a solution of triphenylphosphine (8.30 g, 30.7 mmol) in DCM (40 mL) cooled to -5'C. The flask was protected from the light and a white precipitate was formed after 5min. A solution of the 5-(pyridin-2-yl)pent 4-yn-1-ol (3 g, 18.6 mnol) in DCM (10 mL) was added at a rate to raise the reaction temperature to 5"C at the end of the addition. The reaction solution was cooled to 10 C and stirred for 5h. The colour turned dark green. LCMS shown that the reaction was not completed. As no precipitate appeared, 3/4 of the solvent were removed under low pressure and the mixture cooled down to -10'C, as no precipitate appeared the mixture was concentrated to remove 3/4 of the solvent and then cooled down overnight in the fridge. No precipitate appeared; the reaction was then taken in saturated NaHCO 3 and extracted with DCM. The organic layer was washed with brine, dried over MgS04, filtrated and concentrated. The crude was purified by flash pack chromatography in DCM/MeOH 99.5:0.5 to afford 1.20 g of 2-(5-bromopent-1-ynyl)pyridine contaminated with triphenylphosphine.The compound was used in the next step with no further purification. 242(C) 2-(5-(Pyridin-2-yl)pent-4-vnyl)isoindoline-1,3-dione 2-(5-bromopent-l-ynyl)pyridine (118 mg, 0.525 mmol), isoindoline-1,3-dione (74 mg, 0.5 mmol) and potassium carbonate (140 mg, 1 mmol) were dissolved in acetone (1 mL). The resulting mixture was heated with microwave at 150'C for 15min. The reaction was quenched with water, then acetone was evaporated under reduced pressure. The aqueous layer was extracted with DCM, and the organic layer was washed one time with saturated brine, dried over MgSO 4 , filtrated and concentrated. Purification by flash chromatography pack 15 g silice 40-60, Cyclohexane/AcOEt 50/50 to afford 30 mg of 2-(5-(pyridin-2-y1)pent-4-yny1)isoindoline-1,3-dione (Yield: 20%) as a beige powder (Mp = 127-129'C). LCMS (RT) : 3.46niin; MS (ES+) gave m/z : 291 Rf (Cyclohexane/AcOEt: 50/50) =0.35 1 H-NMR (CDC1 3 ), 8 (ppm): 8.54-8.49 (d, 1H), 7.86-7.83 (in, 2H), 7.72-7.67 (m, 2H), 7.62-7.56 (t, 1H), 7.33-7.29 (d, 1H), 7.19-7.14 (in, 1H), 3.90-3.84 (t, 2H), 2.57-2.52 (t, 2H), 2.10-2.02 (in, 2H) Example 243 2-(6-(Pyridin-2-v1)hex-5-vnv1)phthalazin-1(2H)-one WO 2005/123703 PCT/IB2005/002390 232 243(A) 6-(Pyridin-2-yl)hex-5-yn-1-ol In a dry microwave tube were placed in suspension CuI (76 mg, 0.4 mmol) and triethylamine (14.60 mL, 104 mmol). Then under nitrogen atmosphere, were added the 2-bromopyridine (1.26 g, 8.00 mmol), PdC1 2 (PPh 3
)
2 (281 mg, 0.40 mmol) and triphenyl phosphine polymerbound (530 mg, 1.60 mmol). The suspension was stirred at room temperature for 5 minutes, finally the hex-5-yn-1-ol (790 mg, 8.0 mmol) in 11.5 mL of DMF was added, and the reaction mixture is stirred at room temperature for 30min. The reaction mixture was stirred and heated under micro wave irradiation for 20 min at 120'C. After filtering to remove triphenyl phosphine polymerbound, the triethylamine was concentrated under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NaHCO 3 , H20 and saturated brine. The organic layer was dried over Na 2
SO
4 , filtered and concentrated. Purification over silicagel chromatography (prepacked 50 g silicagel column, DCM/AcOEt : from 100/0 to 50/50 as eluent) to afford 1.32 g of 6-(pyridin-2-yl)hex 5-yn-1-ol (Yield: 94%) as a colorless oil. Rf (DCM/AcOEt: 50/50)= 0.30 LCMS (RT) : 2.09min ; MS (ES+) gave m/z: 176 243(B) 2-(6-Bromohex-1-yny1)pyridine The title compound was prepared in accordance with the general method of Example 242(A), from 6-(pyridin-2-yl)hex-5-yn-1-ol (1.30 g, 7.50 mmol) to afford 138 mg of 2-(6-bromohex-1-ynyl)pyridine (Yield: 8%) as a colorless oil. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt: 50/50 as eluent). LCMS (RT) : 3.94min; MS (ES+) gave m/z : 239 Rf (Cyclohexane/AcOEt: 50/50) =0.40 243(C) 2-(6-(Pyridin-2-yl)hex-5-ynvl)phthalazin-1(2H)-one The title compound was prepared in accordance with the general method of Example 242(B), from 2-(6-bromohex-1-ynyl)pyridine (138 mg, 0.578 mmol) and phthalazin 1(2H)-one (80 mg, 0.55 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH : 98/2 as eluent) to afford 35 mg of 2-(6-(pyridin-2 yl)hex-5-ynyl)phthalazin-1 (2H)-one (Yield : 21%) as a yellow oil. LCMS (RT) : 3.48min; MS (ES+) gave m/z : 304 Rf (DCM/MeOH: 98/2) =0.30 'H-NMR (CDC1 3 ), S (ppm) : 8.55-8.52 (d, 1H), 8.47-8.42 (d, 1H), 8.18 (s, 1H), 7.84 7.75 (m, 2H), 7.72-7.68 (d, 1H), 7.63-7.58 (t, 1H), 7.39-7.35 (d, 1H), 7.20-7.15 (m, 1H), 4.32-4.29 (t, 2H), 2.54-2.51 (t, 2H), 2.07-2.04 (m, 2H), 1.75-1.72 (m, 211) Example 244 N-(4-Chlorophenv)-5-(pyridin-2-yl)pent-4-ynamide 244(A) N-(4-Chlorophenvl)pent-4-ynamide According to the protocol described in Example 12(A), the conversion of 4 chlorobenzenamine (650 mg, 5.10 mmol) afforded 820 mg of N-(4 chlorophenyl)pent-4-ynamide (Yield : 77%) as brownish solid.
WO 2005/123703 PCT/IB2005/002390 233 Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) Rf (100% DCM)= 0.35 INMR (CDC1 3 ), 5 (PPM) : 7.60 (s, 1H), 7.40-6.90 (m, 4H), 2.60-2.40 (m, 4H), 1.95 (s, 1H) 244(B) tert-Butyl 4-chlorophenyl(pent-4-ynoycarbamate The title compound was prepared in accordance with the general method of Example 34(B), from N-(4-chlorophenyl)pent-4-ynamide (820 mg, 3.95 mmol) and (BOC) 2 0 (1.03 g, 4.74 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.13 g of tert-butyl 4-chlorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 94%). Rf (100% DCM) = 0.63 LCMS (RT) : 4.90min; MS (ES+) gave m/z : MH+ -Boc: 208 244(C) tert-Butyl 4-chlorophenv1(5-(pyridin-2-vl)pent-4-vnovl)carbamate To a solution of Cul (7.7 mg, 0.041 mmol) in triethylamine (2.28 mL) were added 2 bromopyridine (129 mg, 0.82 mmol) and (PPh 3
)
2 PdC1 2 (28.7 mg, 0.041 mmol). The reaction mixture was cooled to 0 0 C and tert-butyl 4-chlorophenyl(pent-4 ynoyl)carbamate (250 mg, 0.82 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated under reflux for 3 h. at 70'C Triethylamine was evaporated, water was added and the aqueous phase was extracted twice with DCM. The organic phase was dried over Na 2
SO
4 , filtered and concentrated. The crude residue was purified by flash chromatography (prepacked 25 g silicagel column,Cyclohexane/AcOEt : 70/30 as eluent) to afford 172 mg (Yield : 55%) of tert-butyl 4-chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate as a yellow oil. Rf (Cyclohexane/AcOEt : 70/30)= 0.18 LCMS (RT) : 4.83min; MS (ES+) gave m/z : 385 244(D) N-(4-Chlorophenv)-5-(pyridin-2-vl)pent-4-vnamide According to the protocol described in Example 34(D), the conversion of tert-butyl 4 chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate (172 mg, 0.45 mmol) afford 67 mg of N-(4-cllorophenyl)-5-(pyridin-2-yl)pent-4-ynamide (Yield : 53%) as white powder (Mp = 110-111'C). The crude product was triturated twice with a mixture conatining pentane/isopropyl ether 50/50, to obtain the desired compound as a white powder. LCMS (RT) : 3.63min; MS (ES+) gave m/z: 285 'NMR (CDCl 3 ), 5 (ppm) : 8.55 (s, 1H), 7.70-7.50 (m, 3H), 7.40-7.20 (t, 2H), 7.18 7.05 (m, 2H), 7.00-6.90 (m, 1H), 2.85-2.75 (t, 2H), 2.68-2.58 (t, 2H) Example 245 N-(3-Chlorophenv1)-5-(pyridin-2-v1)pent-4-vnamide 245(A) N-(3-Chlorophenvl3pent-4-vnamide According to the protocol described in Example 12(A), the conversion of 3 chlorobenzenamine (650 mg, 5.10 mmol) afforded 630 mg of N-(3 chlorophenyl)pent-4-ynamide (Yield: 59%) as brownish solid.
WO 2005/123703 PCT/IB2005/002390 234 Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) Rf (100% DCM) = 0.26 245(B) tert-Butyl 3-chlorophenvl(pent-4-ynoyl)carbamate The title compound was prepared in accordance with the general method of Example 34(B), from N-(3-chlorophenyl)pent-4-ynamide_(630 mg, 3.03 mmol) and (BOC) 2 0 (795 mg, 3.64 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column 100% DCM as eluent) to afford 824 mg of tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 88%). LCMS (RT) : 4.93min; MS (ES+) gave m/z : MH+ -Boc: 208 Rf (100% DCM) = 0.57 245(C) tert-Butvl 3-chlorophenvl(5-(pyridin-2-yl)pent-4-ynovl)carbamate The title compound was prepared in accordance with the general method of Example 244(C), from tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) and 2-bromopyridine (129 mg, 0.82 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column cyclohexane/AcOEt : 70/30 as eluent) to afford 226 mg of tert-butyl 3-chlorophenyl(pent-4 ynoyl)carbamate as a brown oil (Yield: 72%). LCMS (RT) : 4.87min; MS (ES+) gave m/z : 385 Rf (Cyclohexane/AcOet : 70/3 0) = 0.18 245(D) N-(3-Chlorophenvl)-5-(pyridin-2-v1)pent-4-ynamide According to the protocol described in Example 34(D), the conversion of tert-butyl 3 chlorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate (226 mg, 0.58 mmol) afford 140 mg of N-(3-chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide (Yield: 84%) as beige powder (Mp = 167.8-168.8'C). The crude product was triturated twice with a mixture containing pentane/isopropyl ether 50/50, to obtain the desired compound as a beige powder. LCMS (RT) : 3.58min; MS (ES+) gave m/z : 285 1 NMR (CDC1 3 ), 6 (ppm) : 8.50 (d, 1H), 7.70-7.10 (m, 8H), 2.85-2.72 (t, 2H), 2.65 2.55 (t, 2H) Example 246 N-(2,4-Difluorophenvl)-5-(pvridin-2-yl)pent-4-ynamide 246(A) N-(2,4-Difluorophenvl)pent-4-ynamide According to the protocol described in Example 12(A), the conversion of 2,4 difluorobenzenamine (658 mg, 5.10 nmol) afforded 630 mg of N-(2,4 difluorophenyl)pent-4-ynamide (Yield: 59%) as brownish solid. Purification over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) Rf (100% DCM) = 0.35 'NMR (CDC1 3 ), 5 (ppm): 8.30-8.10 (m, 1H), 7.40 (s, 1H), 6.90-6.70 (m, 2H), 2.50 (s, 4H), 1.98 (s, 1H).
WO 2005/123703 PCT/IB2005/002390 235 246(B) tert-Butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate The title compound was prepared in accordance with the general method of Example 34(B), from N-(2,4-difluorophenyl)pent-4-ynamide (630 mg, 3.01 mmol) and
(BOC)
2 0 (789 mg, 3.61 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column,100% DCM as eluent) to afford 924 mg of tert-butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 99%). LCMS (RT) : 4.82min; MS (ES+) gave m/z : MH+ -Boc: 210) Rf (100% DCM) = 0.63 246(C) tert-Butyl 2,4-difIuorophenyl(5-(pyridin-2-lpent-4-ynoyl)carbamate The title compound was prepared in accordance with the general method of Example 244(C), from tert-butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate_(250 mg, 0.82 mmol) and 2-bromopyridine (129 mg, 0.82 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column cyclohexane/AcOEt : 70/30 as eluent) to afford 193 mg of tert-butyl 2,4-difluorophenyl(5-(pyridin-2 yl)pent-4-ynoyl)carbamate as a brown oil (Yield : 61%). LCMS (RT) : 4.72min; MS (ES+) gave m/z : 387 Rf (Cyclohexane/AcOet : 70/3 0)= 0.18 246(D) N-(2,4-Difluoropheny1)-5-(pyridin-2-yl)pent-4-ynamide According to the protocol described in Example 34(D), the conversion of tert-butyl 2,4-difluorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate (193 mg, 0.50 mmol) afford 123 mg of N-(2,4-difluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide (yield 86%) a beige powder (Mp = 132-133.2'C). The crude product was triturated twice with a mixture conatining pentane/isopropyl ether 50/50, to obtain the desired compound as a beige powder. LCMS (RT) : 3.20min; MS (E$+) gave m/z : 287. 'NMR (CDC1 3 ), 5 (ppm) : 8.50 (d, 1H), 8.30-8.10 (in. 1H), 7.70-7.10 (in, 411), 6.90 6.70 (m, 2H), 2.90-2.80 (t, 2H), 2.70-2.60 (t, 2H). Example 247 2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-l-amine (39 mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzoyl chloride (50 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 13.5 mg (43 pmol, 19%) of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 ynyl)benzamide as a colorless oil. LCMS (RT) : 3.52min; MS (ES+) gave m/z : 317.1, 319.1. Example 248 2-Chloro-N-(4-(6-(fluoromethyl)pvridin-2-yl)but-3-ynyl)benzenesulfonamide The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-l-amine (39 mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzenesulfonyl chloride (60 mg, 0.28 mmol). The WO 2005/123703 PCT/IB2005/002390 236 crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 14.4 mg (41 ptmol, 19%) of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3 ynyl)benzenesulfonamide as an orange oil. LCMS (RT) : 3.92min; MS (ES+) gave m/z: 353.1, 355.1. Example 249 2-(4-(4-(4-Fluoropheny)-2H-1,2,3-triazol-2-yl)but-1-vny13pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150 mg, 0.70 mmol, Example 254(B)) and 2-bromopyridine (122 mg, 0.77 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 84 mg (0.29 mmol, 41%) of 2-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a yellow solid (M.P. = 83.5-84.5'C). LCMS (RT) : 4.07min; MS (ES+) gave m/z : 293.1. Rf (DCM/MeOH 98:2) = 0.2. 1 H-NMR (CDC1 3 ), 5 (ppm) : 3.16 (t, J=7.2, 2H), 4.71 (t, J=7.2, 2H), 7.08-7.16 (2H), 7.21 (ddd, J=1.2, 4.8 and 7.8, 1H), 7.35 (d, J=7.8, 1H), 7.58-7.65 (m, 1H), 7.73-7.78 (2H), 7.81 (s, 111), 8.55 (d, J=4.5, 1H). Example 250 2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150 mg, 0.70 mmol, Example 254(B)) and 2-bromo-6-(fluoromethyl)pyridine (146 mg, 0.77 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5 to 99:1) to yield 101 mg (0.31 mmol, 45%) of 2 (fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a yellow solid (M.P. = 84-86'C). LCMS (RT) : 4.44min; MS (ES+) gave m/z: 325.2. Rf (DCM/MeOH 98:2) = 0.3. 1 H-NMR (CDC1 3 ), 5 (ppm) : 3.16 (t, J=7.5, 2H), 4.71 (t, J=7.5, 2H), 5.36-5.54 (m, 2H), 7.08-7.16 (2H), 7.31 (d, J=7.8, 1H), 7.40 (d, J=7.8, 1H), 7.66-7.72 (m, 1H), 7.73 7.79 (2H), 7.81 (s, 1H). Example 251 2-Chloro-N-(4-(pyridin-2-vl)but-3-vnvl)benzenesulfonamide 251(A) 2-(4-(Pyridin-2-v)but-3-vnvl)isoindoline-1,3-dione The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (453 mg, 2.21 mmol) and 2-(but-3-ynyl)isoindoline-1,3-dione (400 mg, 2.01 mmol, Example 189(B)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 70:30) to yield 250 mg (0.90 mmol, 45%) of 2 (4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as. LCMS (RT) : 3.43min; MS (ES+) gave m/z: 277.1.
WO 2005/123703 PCT/IB2005/002390 237 251(B) 4-(Pyridin-2-yl)but-3-yn-1-amiine The title compound was prepared in accordance with the general method of Example 189(D), from 2-(4-(pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione (250 mg, 0.90 mmol) to yield 32 mg (0.22 mmol, 24%) of 4-(pyridin-2-yl)but-3-yn-1-amine as a white solid. 251(C) 2-Chloro-N-(4-(pyridin-2-vl)but-3-vnyl)benzenesulfonamide The title compound was prepared in accordance with the general method of Example 184, from 4-(pyridin-2-yl)but-3-yn-1-amine (16 mg, 0.11 nnol) and 2 chlorobenzene-1-sulfonyl chloride (30 mg, 0.14 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 11.2 mg (35 tmol, 32%) of 2-chloro-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide as a brown oil. LCMS (RT) : 3.48min; MS (ES+) gave m/z : 321.1, 323.1. Example 252 5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluoro-2-methyl-phenylpent-4-vnamide 252(A) [5-(6-Fluoromethl-pyridin-2-yl)-pent-4-ynov11(4-fluoro-2-methyl-phenl) carbamic acid tert-butyl ester The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (150 mg, 0.79 mmol, Example 190(E)) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbanic acid tert-butyl ester (241 mg, 0.79 mmol, 188(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 260 mg (0.63 mmol, 79%) of [5 (6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl-phenyl)-carbamic acid tert-butyl ester as a white solid. Rf (cyclohexane/AcOEt 4:1) = 0.2. 252(B) 5-(6-(Fluoromethyl)pyridin-2-vl1-N-(4-fluoro-2-methyl-phenyllpent-4 vnamide The title compound was prepared in accordance with the general method of Example 34(D), from [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-2-methyl phenyl)-carbamic acid tert-butyl ester (260 mg, 0.63 mmol). After the work-up, the crude residue was washed with diisopropyl ether to yield 190 mg (0.60 mmol, 97%) of 5-(6-(fluoromethyl)pyridin-2-yl)-N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide as a white powder (M.P. = 122-125'C). LCMS (RT) : 3.08min; MS (ES+) gave m/z : 3 15.1. 'NMR (CDCl 3 ), 6 (ppm) : 2.23 (s, 3H), 2.72 (t, J=7.5, 2H), 2.90 (t, J=7.5, 2H), 5.36 5.54 (m, 2H), 6.84-6.94 (2H), 7.32 (d, J=7.5, 1H), 7.40 (d, J=7.5, 1H), 7.60-7.79 (2H). Example 253 5-(4-Fluoro-phenyl)-1-(4-pyridin-2-vl-but-3-vnyl)-lH-pyridin-2-one 253(A) 5-Bromo-1-(4-pyridin-2-v1-but-3-vnyl> 1H-pyridin-2-one The title compound was prepared in accordance with the general method of Example 109(D), from 4-(pyridin-2-yl)but-3-yn-1-ol (700 mg, 4.76 mmol, Example 3(A)) and 5-bromo-1H-pyridin-2-one (870 mg, 5.00 mmol). The crude residue was purified by WO 2005/123703 PCT/IB2005/002390 238 flash chromatography (cyclohexane/AcOEt 9:1) to yield 334 mg (1.10 mmol, 23%) of 5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one. 253(B) 5-(4-Fluoro-phenyl)-1-(4-pyridin-2-vl-but-3-ynyl)-1H-pyridin-2-one The title compound was prepared in accordance with the general method of Example 83, from 5-bromo-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one (50 mg, 0.16 mmol) and 4-fluorophenylboronic acid (35 mg, 0.25 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 18 mg (57 ptmol, 34%) of 5-(4-fluoro-phenyl)-1-(4-pyridin-2-yl-but-3-ynyl)-1H-pyridin-2-one. LCMS (RT): 4.66min; MS (ES+) gave m/z : 319.2. Example 254 2-(Fluoromethyl)-6-(4-(4-(4-fluorophenvl)-1H-1,2,3-triazol-1-yl)but-1-ynvl)pyridine 254(A) 4-(4-Fluorophenyl)-2H-1,2,3-triazole The title compound was prepared in accordance with the general method of Example 179(A), from (E)-l-fluoro-4-(2-nitrovinyl)benzene (2.00 g, 12.0 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 1.08 g (6.62 mmol, 55%) of 4-(4-fluorophenyl)-2H-1,2,3-triazole as an orange solid. Rf (cyclohexane/AcOEt 4:1) = 0.1. 254(B) 1-(But-3-vnyl)-4-(4-fluorophenvl)-1H-1,2,3-triazole and 2-(but-3-ynvl)-4-(4 fluorophenvl)-2H-1,2,3-triazole The title compounds were prepared in accordance with the general method of Example 109(D), from 4-(4-fluorophenyl)-2H-1,2,3-triazole (1.08 g, 6.62 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5 to 80:20) to yield 200 mg (0.92 mmol, 14%) of 1-(but-3-ynyl)-4-(4-fluorophenyl)-1H 1,2,3-triazole as a yellow solid and 300 mg (1.40 mmol, 21%) of 2-(but-3-ynyl)-4-(4 fluorophenyl)-2H-,2,3-triazole as a orange solid. 1-(But-3-nyl)-4-(4-fluoropheny1)-1H-1,2,3-triazole: LCMS (RT) : 3.57min; MS (ES+) gave m/z : 216.1. Rf (cyclohexane/AcOEt 4:1)= 0.1. 2-(But-3-vny)-4-(4-fluorophenl)-2H-,2,3-triazole: LCMS (RT) : 4.20min; MS (ES+) gave m/z: 216.1. Rf (cyclohexane/AcOEt 4:1)= 0.5. 254(C) 2-(Fluoromethyl)-6-(4-(4-(4-fluorophenvl)-1H-1,2,3-triazol-1-yl)but-1 ynyl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-lH-1,2,3-triazole (100 mg, 0.47 mmol) and 2-bromo-6-(fluoromethyl)pyridine (97 mg, 0.51 mmol, Example 190(E)). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 32 mg (0.10 mmol, 21%) of 2-(fluoromethyl)-6-(4-(4-(4 fluorophenyl)-lH-1,2,3-triazol-1 -yl)but-1-ynyl)pyridine as a yellow solid (M.P. 100-103-C). LCMS (RT) : 3.90min; MS (ES+) gave m/z: 325.1. Rf (DCM/MeOH 98:2) = 0.2.
WO 2005/123703 PCT/IB2005/002390 239 H-NMR (CDC1 3 ), 6 (ppm) : 3.10 (t, J=6.6, 2H), 4.67 (t, J=6.6, 2H), 5.37-5.55 (in, 2H), 7.08-7.15 (2H), 7.30 (d, J=8.1, 1H), 7.42 (d, J=8.1, 1H), 7.67-7.74 (m, 1H), 7.77 7.83 (2H), 7.93 (s, 1H). Example 255 8-Chloro-2-(4-(pyridin-2-yl)but-3-yny)-imidazo[1,2-alpyridine 255(A) 8-Chloro-2-(4-(trimethylsilvl)but-3-Yny)-imidazo1,2-alpyridine The title compound was prepared in accordance with the general method of Example 223(D), from 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (4.96 g, 20.1 mmol, Example 223(C)) and 3-chloropyridin-2-amine (1.29 g, 10.0 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 2.00 g (7.22 mmol, 72%) of 8-chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine as a brown solid. 'HT-NMR (CDC1 3 ), 6 (ppm) : 0.14 (s, 12H), 2.66 (t, J=6.9, 2H), 3.06 (t, J=7.2, 2H), 6.69 (t, J=7.2, 1H), 7.21 (d, J=7.5, 1H), 7.53 (s, 1H), 7.99 (d, J=6.6, 1H). 255(B) 2-(But-3-ynyl)-8-chloro-imidazo[l,2-alpyridine The title compound was prepared in accordance with the general method of Example 108(B), from 8-chloro-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (2.00 g, 7.22 mmol). The crude residue was taken in Et 2 O, filtered and concentrated to yield 1.09 ing (5.31 mmol, 74%) of 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine as a yellow solid. 'H-NMR (CDC1 3 ), 8 (ppm) : 1.97 (t, J=2.7, 1H), 2.66 (t, J=7.2, 2H), 3.07 (t, J=6.9, 2H), 6.69 (t, J=6.9, 1H), 7.21 (d, J=7.2, 111), 7.54 (s, 1H), 8.0 (d, J = 6.9, 1H). 255(C) 8-Chloro-2-(4-(pyridin-2-vl)but-3-vnvl)-imidazo[1,2-alpyridine The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol) and 2 bromopyridine (405 mg, 2.57 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 293 ing (1.04 mmol, 43%) of 8 chloro-2-(4-(pyridin-2-y)but-3-yny)H-imidazo[1,2-alpyridine as a white solid (M.P. = 106-107-C). LCMS (RT) : 2.22nin; MS (ES+) gave m/z : 282.1, 284.0. Rf (DCM/MeOH 98:2) = 0.1. 'H-NMR (CDC1 3 ), S (ppm) : 2.92 (t, J=7.2, 2H), 3.18 (t, J=7.2, 2H), 6.65-6.71 (in, 1H), 7.15-7.24 (2H), 7.35 (d, J=7.8, 1H), 7.57-7.63 (2H), 8.01 (d, J=7.2, 1H), 8.52 8.56 (in, 111). Example 256 8-Chloro-2-(4-(6-(fluoromethvl)pyridin-2-vl)but-3-ynvl)-imidazo[1,2-alpyridine The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-8-chloro-imidazo[1,2-a]pyridine (500 mg, 2.44 mmol, Example 255(B)) and 2-bromo-6-(fluoromethyl)pyridine (487 mg, 2.57 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 420 mg (1.34 nmmol, 55%) of 8-chloro-2-(4-(6- WO 2005/123703 PCT/IB2005/002390 240 (fluoroinethyl)pyridin-2-yl)but-3-yny)-imidazo[1,2-a]pyridine as a slightly yellow solid (M.P. = 73-74.5'C). LCMS (RT) : 2.57min; MS (ES+) gave n/z : 314.1, 316.1. Rf (DCM/MeOH 98:2)= 0.2. 'H-NMR (CDC1 3 ), a (ppm) : 2.92 (t, J=7.2, 2H), 3.18 (t, J=7.2, 2H), 5.36-5.55 (m, 2H), 6.66-6.73 (m, 1H), 7.22 (dd, J=0.9 and 7.8, 1H), 7.32 (d, J=8.1, 1H), 7.37 (d, J=7.8, 1H), 7.57 (s, 1H), 7.65-7.72 (m, 1H), 8.00 (dd, J=0.9 and 6.6, 1H). Example 257 2-(4-(4-(4-Fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-Y1)but-1-vnyl)pyridine 257(A) 4-(4-Fluorophenvl)-5-methyl-2H-1,2,3-triazole The title compound was prepared in accordance with the general method of Example 179(A), from (E)-1-fluoro-4-(2-nitroprop-1-enyl)benzene (1.01 g, 5.60 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 407 mg (2.30 mmol, 41%) of 4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole as a slightly yellow solid. Rf (cyclohexane/AcOEt 4:1) = 0.05. 257(B) 2-(But-3-ynyl)-4-(4-fluoropheny1)-5-methyl-2H-1,2,3-triazole and 1-(but-3 vnyl)-4-(4-fluorophenvl)-5-methv1l2H-1,2,3-triazole The title compounds were prepared in accordance with the general method of Example 109(D), from 4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole (407 mg, 2.30 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5 to 80:20) to yield 265 mg (1.16 mmol, 51%) of 2-(but-3-ynyl)-4-(4 fluorophenyl)-5-methyl-2H-1,2,3-triazole as a colorless oil and 87 mg (0.38 mmol, 17%) of 1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole as a white solid. 2-(But-3-vnyl)-4-(4-fluorophenyl)-5-methyl-2H-1.2,3-triazole: LCMS (RT) : 4.32min; MS (ES+) gave m/z : 230.1. Rf (cyclohexane/AcOEt 4:1) 0.4. 1 -(But-3-ynyl)-4-(4-fluoropheny)-5-methyl- 1H-1,2,3-triazole: LCMS (RT) : 3.63min; MS (ES+) gave m/z: 230.1. Rf (cyclohexane/AcOEt 4:1) = 0.1. 257(C) 2-(4-(4-(4-Fluoropheny1)-5-methyl-2H-1,2,3-triazol-2-y)but-1-ynvllpyridine The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazole (265 mg, 1.16 mmol) and 2-bromopyridine (201 mg, 1.27 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 306 mg (1.00 mmol, 86%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-2H-1,2,3-triazol-2-yl)but-1 ynyl)pyridine as a brown oil. LCMS (RT) : 4.19min; MS (ES+) gave m/z : 307.1. Rf (DCM/MeOH 98:2) = 0.2. 'H-NMR (CDC1 3 ), 5 (ppm) : 2.46 (s, 3H), 3.12 (t, J=7.2, 2H), 4.63 (t, J=7.2, 2H), 7.08-7.16 (2H), 7.18-7.23 (m, 1H), 7.36 (dd, J=0.9 and 7.5, 1H), 7.58-7.67 (3H), 8.52 8.56 (m, 1H).
WO 2005/123703 PCT/IB2005/002390 241 Example 258 2-(4-(4-(4-Fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-vl)but-1-ynvl)pvrirlin The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-lH-1,2,3-triazole (87 mg, 0.38 mmol, Example 257(B)) and 2-bromopyridine (66 mg, 0.42 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 68 mg (0.22 mmol, 58%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-1H-1,2,3 triazol-1-yl)but-1-ynyl)pyridine as a white powder (M.P.= 130-131 C). LCMS (RT) : 3.56min; MS (ES+) gave m/z : 307. Rf (DCM/MeOH 98:2) = 0.2. 'H-NMR (CDCl 3 ), 5 (ppm) : 2.53 (s, 3H), 3.11 (t, J=7.2, 2H), 4.57 (t, J=7.2, 2H), 7.09-7.17 (2H), 7.20-7.25 (in, 1H), 7.34 (d, J=7.8, 1H), 7.59-7.70 (3H), 8.55 (d, J=4.5, 1H). Example 259 2-(4-(4-(2-Chlorophenyl)-2H-1,2,3-triazol-2-yl)but-1-vnvl)pyridine 259(A) 4-(2-Chlorophenvl)-2H-1,2,3-triazole The title compound was prepared in accordance with the general method of Example 179(A), from (E)-l-chloro-2-(2-nitrovinyl)benzene (2.06 g, 11.2 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 1.05 g (5.85 mmol, 52%) of 4-(2-chlorophenyl)-2H-1,2,3-triazole as an orange solid. Rf (cyclohexane/AcOEt 4:1) = 0.1. 259(B) 2-(But-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole and 1-(but-3-ynv1)-4-(2 chlorophenyl)-1H-1,2.3-triazole The title compounds were prepared in accordance with the general method of Example 109(D), from 4-(2-chlorophenyl)-2H-1,2,3-triazole (1.05 g, 5.85 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 95:5 to 80:20) to yield 660 mg (2.85 mmol, 50%) of 2-(but-3-ynyl)-4-(2-chlorophenyl)-2H 1,2,3-triazole as a yellow oil and 400 mg (1.73 mmol, 30%) of 1-(but-3-ynyl)-4-(2 chlorophenyl)-1H-1,2,3-triazole as a yellow oil. 2-(But-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole: LCMS (RT) : 4.47min; MS (ES+) gave m/z : 232.1. Rf (cyclohexane/AcOEt 4:1) 0.4. 1 -(But-3-vnyl)-4-(2-chlorophenyl)-1H-1,2,3-triazole: LCMS (RT) : 3.86min; MS (ES+) gave m/z : 232.1. Rf (cyclohexane/AcOEt 4:1)= 0.2. 259(C) 2-(4-(4-(2-Chlorophenvl)-2H-1,2,3-triazol-2-yl)but-1-vnyl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole (200 mg, 0.86 mnol) and 2-bromopyridine (150 mg, 0.95 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 120 mg (0.39 mmol, 45%) of 2-(4 (4-(2-chlorophenyl)-2H-1,2,3-triazol-2-y)but-1-ynyl)pyridine as a brown oil. LCMS (RT) : 4.34min; MS (ES+) gave m/z: 309.1, 311.1. Rf (DCM/MeOH 98:2) = 0.3.
WO 2005/123703 PCT/IB2005/002390 242 'H-NMR (CDCl 3 ), 5 (ppm) : 3.18 (t, J=7.5, 2H), 4.75 (t, J=7.5, 2H), 7.21 (ddd, J=1.2, 4.8 and 7.5, 1H), 7.28-7.39 (3H), 7.45-7.48 (m, 1H), 7.58-7.65 (m, 1H), 7.85-7.88 (m, 1H), 8.14 (s, 1H), 8.55 (d, J=4.8, 1H). Example 260 2-(4-(4-(2-Chlorophenyl)-1H-1,2,3-triazol-1-yl)but-1-v-nl)pyridine The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(2-chlorophenyl)-IH-1,2,3-triazole (200 mg, 0.86 mmol, Example 259(B)) and 2-bromopyridine (150 mg, 0.95 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 93.4 mg (0.30 mmol, 35%) of 2-(4-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a yellow oil. LCMS (RT) : 3.74min; MS (ES+) gave m/z : 309.1, 311.1. Rf (DCM/MeOH 98:2)= 0.2. IH-NMR (CDC1 3 ), 6 (ppm) : 3.12 (t, J=6.6, 2H), 4.70 (t, J=6.6, 2H), 7.20-7.25 (in, 111), 7.26-7.29 (m, 1H), 7.34-7.44 (3H), 7.59-7.66 (m, 1H), 8.24 (dd, J=1.8 and 7.5, 1H), 8.40 (s, 1H), 8.56 (d, J=4.8, 1H). Example 261 6,8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-vl)but-3-vnvl)H-imidazor1,2-alpyridine 261(A) 6,8-Difluoro-2-(4-(trimethylsilvl)but-3-ynyl)H-imidazo[1,2-alpyridine The title compound was prepared in accordance with the general method of Example 223(D), from 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (2.0 g, 8.1 mmol, Example 223(C)) and 3,5-difluoropyridin-2-amine (0.56 g, 4.30 mmol). The crude residue was purified by flash chromatography (DCM 100% to DCM/MeOH 99:1) to yield 200 mg (2.02 mmol, 18%) of 6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2 a]pyridine as a brown solid. 261(B) 2-(But-3-ynyl)-6,8-difluoroH-imidazoF1,2-alpvridine The title compound was prepared in accordance with the general method of Example 108(B), from 6,8-difluoro-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine (200 mg, 2.02 mmol). The crude residue was taken in ether, filtered and concentrated to yield 150 mg (0.73 mmol, 100%) of 2-(but-3-ynyl)-6,8-difluoroH-imidazo[1,2 a]pyridine as a brown solid. 261(C) 6,8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynvl)H-imidazo[1,2 alpyridine The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-6,8-difluoroH-imidazo[1,2-a]pyridine (150 mg, 0.73 mmol) and 2-bromo-6-(fluoromethy)pyridine (200 mg, 1.05 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 110 mg (0.35 mmol, 48%) of 6,8-difluoro-2-(4-(6-(fluoromethyl)pyridin-2 yl)but-3-ynyl)H-inidazo[1,2-a]pyridine as a yellow solid (M.P.=1 13-114'C). LCMS (Tr) : 3.28min; MS (ES+) gave m/z: 316.2. Rf (DCM/MeOH 98:2) = 0.1.
WO 2005/123703 PCT/IB2005/002390 243 'H-NMR (CDC1 3 ), 6 (ppm) : 2.92 (t, J=7.2, 2H), 3.14 (t, J=7.8, 2H), 5.46 (d, J=46.8, 211), 6.83-6.89 (in, 111), 7.31 (d, J=7.8, 1H), 7.38 (d, J=7.5, 1H), 7.58 (d, J=3.0, 1H), 7.70 (t, J=7.5, 1H), 7.89 (m, 1H). FORMULATION EXAMPLES Typical examples of recipes for the formulation of the invention are as follows: 1) Tablets Compound of the example 256 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg In this example, the compound of the example 256 can be replaced by the same amount of any of the described examples 1 to 261. 2) Suspension An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the described example, 50 ing of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 ing of sorbitol and water ad 1 ml. 3) Injectable A parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol and water. 4) Ointment Compound of the example 256 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g In this example, the compound 256 can be replaced by the same amount of any of the described examples 1 to 261. Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the thus described invention may be varied in many ways by those skilled in the art.

Claims (43)

1. A compound of formula I W (CH 2 )n-X I Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein: W is a 5-, 6-heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R2 R
2 R 2 O I R3 N x' R%3 R I RR
3 -N2 R R SNR N N R 1 R 1 R R 2 R1 R 1 R2N> N NNI' N N R R R 2 N R R 4 NA A R3 N N N 3 R 2 W 1 R 2 R 1 R 2 R1 2 'R R1, R2, R3, R 4 , Rs and A"' are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-CrC 6 -alkyl, O-Cl-C 6 -alkylhalo, 0-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C 7 -cycloalkyl, 0-CI-C 6 -alkyl heteroaryl, O-CrC 6 -alkylaryl, Co-C 6 -alkyl-0R 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-CrC 6 -alkyl, 0-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0 heteroaryl, heteroaryl, CI-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 alkylaryl, CrC-alkylhalo-OR, C 3 -C 6 -alkynyl-OR6, C 3 -C 6 -alkcnyl OR 6 , Co-Cs-alkyl-S-R 6 , 0-C 2 -C 6 -alkyl-S-R 6 , Co-C 6 -alkyl-S(=0)-R 6 , 0 C 2 -C 6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=0) 2 -R 6 , 0-C 1 -C 6 -alkyl-S(=0) 2 R6, Co-C-alkyl-NR R, 0-C 2 -C 6 -alkyl-MN 6 R 7 , Co-C 6 -alkyl S(=0) 2 NRR 7 , Co-C-alkyl-NR 6 -S(=0) 2 R 7 , 0-CI-C 6 -alkyl S(=O) 2 NR 6 R 7 , 0-CrCralkyl-N -S(=0)2R7, Co-C 6 -alkyl-C(=O) NR 6 R 7 , Co-C 6 -alkyl-NR 6 C(=O)-R 7 , O-C 1 -C 6 -alkyl-C(=0)-NReR 7 , 0- WO 2005/123703 PCT/IB2005/002390 245 C 2 -C 6 -alkyl-NR 6 C(=O)-R 7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl C(=O)-OR 6 , O-C 2 -C 6 -alkyl-OC(=O)-R 6 , O-C 1 -C 6 -alkyl-C(=O)-OR6 Co-C 6 -alkyl-C(=O)-R 6 , O-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR6_ C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=0)-NR 6 R 7 or Co-C 6 -alkyl-NR 6 -C(=O) NR 7 R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C2-C6 alkenyl, O-CI-C 6 -alkyl, 0-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, 0-C 3 -C 6 alkenyl, O-C 3 -C7-cycloalkyl, O-Cl-C 6 -alkyl-heteroaryl, O-ClC6 alkylaryl, Cl-C6-alkylaryl, C3-C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Ci-C6 alkyl, O-C 3 -C 7 -cycloalkyl-CI-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, Cr-C6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by I to 5 Am groups; m is an integer from 1 to 5; n is an integer from 1 to 6; X is selected from an optionally substituted CI-C 6 -alkyl, Ce-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, 0-Co-C 6 -alkyl, O-Cl-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, 0-C 3 -C 6 -alkenyl, 0-C 3 -C 7 -cycloalkyl, C-C 6 -alkyl-0, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C-C6 alkylhalo-O, C 3 -C 6 -alkynyl-0, C 3 -C 6 -alkenyl-0, Co-C 6 -alkyl-S, Co-C6 alkyl-S(=0), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6 -NRS(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=0)-NR 9 , Co-C 6 -alkyl NRC(=O), Co-C 6 -alkyl-OC(=0), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=0), Co-C 6 -alkyl-NR-C(=0)-0, Co-C 6 -alkyl-O-C(=0)-NR 9 , Co-C6 alkyl-NR 9 -C(=0)-Nk 10 , Co-C6-alkyl-N 9 -C(=NRD)NR 1 , Co-C 6 -alkyl (C=NR 9 )NR'U, Co-C 6 -alkyl-C(=0)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NRO-Co-C6-alkyl, Co-C6-alkyl-C(=NOR 9 ) or Co-C6-alkyl-0-N=CR 9 substituents; R 9 , R 0 and R" are each independently selected from hydrogen, an optionally substituted CI-C6-alkyl, Cr-C 6 -alkylhalo, C 2 -C 6 -alkynyL, C2 C6-alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalky-C-C 6 -alky1, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; W' denotes a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0 and S, which ring may optionally WO 2005/123703 PCT/IB2005/002390 246 be fused with a 5- or 6- inembered ring containing one or more atoms independently selected from C, N, 0 and S, provided that W' is a aryl, heteroaryl or heterocycle selected from the group of formula: 0 Gq q S N S G G Gr- N G4 G -,\ GN O ~ NNGG G G- NB G4N ~ G42G4- N Gq-- (IN G q~ :Z GqGq ~ N G4 4- - GR- - G 1 GG Gq N -1 GN- N GN G N -- N G ~ N - G Gq N G- G- G Gq- GI N~ N -- I N ~ N- N N Gqq L,N N~ N2 G NN o 0 N. C Gq-C I N' G I G G Z"7 \10 ~ NN 0 ~ Zz~ Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C 6 alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Ci-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C3-C 6 -alkenyl, O-C 2 -C 6 -alkyl OR 12 , O- -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C 1 -C 6 alkylaryl, Co-C 6 -alkyl-OR , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Cr C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-Cr-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, O-aryl, C,-C 6 -alkylaryl, C-C 6 -alkylhalo OR1 2 , C 3 -C 6 -alkynyl-OR 2 , C 3 -C 6 -alkenyl-OR1 2 , Co-C 6 -alkyl-S-R 2 , O C 2 -C 6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R, O-C 2 -C 6 -alkyl-S(=O)-R, Co-C 6 -alcyl-S(=O) 2 -R 2 , O-CI-C 6 -alkyl-S(=O) 2 -R1 2 , Co-C 6 -alkyl NR' 2 R", O-C 2 -C 6 -alkyl-NR1 2 R", Co-C 6 -alkyl-S(=0) 2 NR 1 2 R", Co-C 6 alkyl-NR1 2 -S(=0) 2 R 1 3 , O-Ce-C 6 -alkyl-S(=0) 2 NR 2 R 1 3 , O-C 2 -C 6 -alkyl NR-S(=0)2RI Co-C 6 -alkyl-C(=O)-NR 12 R 3 , Co-C 6 -alkyl NR 12 C(=O)-R 1, O-C-C 6 -alkyl-C(=O)-NR1 2 R1 3 , O-C 2 -C 6 -alkyl NR 2 C(=O)-R 3 , Co-C 6 -alkyl-OC(=O)-Rl 2 , Co-C 6 -alkyl-C(=0)-OR1 2 , O-C 2 -C 6 -alkyl-OC(=O)-R1 2 , O-C-C 6 -alkyl-C(=O)-OR 1 2 , Co-C 6 -alkyl C(=O)-R 2 , O-C-C 6 -alkyl-C(=O)-R 2 , Co-C 6 -alkyl-NR 2 _-C(=O)-OR1 3 , WO 2005/123703 PCT/IB2005/002390 247 Co-C 6 -alkyl-O-C(=O)-NR 12 R 13 or Co-C 6 -alkyl-NR- 12 C(=O)-NR"R 14 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, Cr-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, 0-Cr-C 6 -alkyl, 0-C-C 6 -alkylhalo, O-C3-C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-Cl-C6-alkyl-heteroaryl, 0-C-C 6 alkylaryl, C 3 -C 7 -cycloalkyl, C3-C7-cycloalkyl-C-C 6 -alkyl, O-C 3 -C 7 cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, CI-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5; R 12 , R 13 and R 1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-Cl-C 6 -alkyl, heteroaryl, C-C6-alkyl-heteroaryl, aryl; z9, ZI, z11, z12, z 13 , Z 1 4 , z15, z16 and Z1 7 are each independently selected from the group consisting of -C=, -C=C-, -C(=0)-, -C(=S)-, C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5Gq groups; B1, B2 and B3 are each selected independently from C, C=C, C=N, S, 0 or N which may further be substituted by one G4 group; Any N may be an N-oxide; provided that: when X is independently selected from NR 15 , 0, S or an optionally substituted CI-C 6 -alkyl, n is 1, W is an optionally substituted 2 pyridinyl and R 15 is independently selected from hydrogen, an optionally substituted Ci-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 C 6 -alkenyl, C3-C 7 -cycloalkyl, C3-C7-cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C6-alkyl-heteroaryl or aryl, W' can not be an optionally substituted aryl; when X is 0, n is 1 and W' is an optionally substituted aryl or heteroaryl, W can not be an optionally substituted 3-pyridazinyl or 4 pyrimidinyl; when X is CH 2 , n is 1 and W' is aryl, W can not be 2-phenyloxazol-4 yl, 4-phenyloxazol-2-yl,
4-(3-(benzyloxy)propyl)-oxazol-2-yl, 4 phenylthiazol-2-yl, 4-methylthiazol-2-yl or benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl; WO 2005/123703 PCT/IB2005/002390 248 when X is 0, n is 1 and W is an optionally substituted pyridinyl, W' can not be an optionally substituted 2-pyridinyl; when X is CH 2 , n is 2 and W' is aryl, W can not be 4-imidazolyl. 2. A compound according to claim 1 having the formula II X II Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from a group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R2 R 2 ROR3- R R R R 1 3 - RRR Os R-<x. -<\ N N N R I P 2 / ) 2 N 1 Q kR ~ N0> N R1 S I DN N-0 R22 N RR R 3 R 3 R N N R 2 R 1 R 2 R 1 R2 R 3 ~ P R 3 ~ 2 Zs3 R' N R' RNm R~ N R N N- R N 3)~- 4z R, R 2 ,R 3 , R 4 , R 5 and A m are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C6-alkynyl, C 2 -C 6 alkenyl, O-CI-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, -O-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C 7 -cycloalkyl, O-C 1 -C 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, O-C3-C7-cycloalkyl-C-C 6 -alkyl, 0 heteroaryl, heteroaryl, C-C6-alkyl-heteroaryl, aryl, 0-aryl, C 1 -C 6 alkylaryl, C-C 6 -alkylhalo-OR 6 , C-C 6 -alkynyl-OR', C 3 -C 6 -alkenyl- WO 2005/123703 PCT/IB2005/002390 249 OR 6 , Co-C 6 -alkyl-S-R 6 , O-C 2 -C 6 -alkyl-S-R 6 , CO-C 6 -alkyl-S(=O)-R 6 , O C 2 -C 6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=O) 2 -R 6 , O-Ci-C6-alkyl-S(=0)2 R6, Co-C 6 -alkyl-NR 6 R 7 , O-C 2 -C 6 -alkyl-NRR7, Co-C 6 -alkyl S(=O) 2 NR 6 R 7 , Co-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , O-C 1 -C 6 -alkyl S(=0) 2 NRR 7 , O-C1-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , Co-C 6 -alkyl-C(=O) NR 6 R 7 , Co-C 6 -alkyl-NR 6 C(=O)-R 7 , O-C1-C 6 -alkyl-C(=O)-NR 6 R7, O C 2 -C 6 -alkyl-NR 6 C(=O)-R 7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl C(=O)-OR 6 , O-C2-C 6 -alkyl-OC(=O)-R 6 , O-CI-C 6 -alkyl-C(=O)-0R 6 , Co-C 6 -alkyl-C(=O)-R 6 , O-CI-C6-alkyl-C(=O)-R, Co-C 6 -alkyl-NR C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR 6 R or Co-C 6 -alkyl-NR 6 -C(=O) NR R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1 -C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-CI-C 6 -alkyl, O-Ci-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C1-C 6 -alkyl-heteroaryl, 0-C1-C 6 alkylaryl, C1-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C3-C7-cycloalkyl-C1-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, 0-heteroaryl, heteroaryl, C1 C 6 -alkyl-heteroaryl, aryl, 0-aryl; Ri, RI and Ri are each independently selected from the group consisting of hydrogen, an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C1-C 6 -alkyl, heteroaryl, C 1 -C 6 -alkyl-heteroaryl, aryl; ZI, Z2, Z3, Z4, ZI, Z6, Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A! m groups; m is an integer from 1 to 5; X is selected from an optionally substituted C 1 -C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C1-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 -cycloalkyl, C 1 -C 6 -alkyl-O, C 3 -C 7 -cycloalkyl, C 3 -C7-cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C 1 -C 6 alkylhalo-O, C 3 -C 6 -alkynyl-0, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=O) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6 -NR 9 S(=O) 2 , Co-C 6 -alkyl-S(=O) 2 NR 9 , Co-C 6 -alkyl-C(=0)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR' 0 , Co-C 6 -alkyl-NR 9 -C(=NR 0 )NR , Co-C 6 -alkyl (C=NR 9 )NR", Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR substituents; R?, R' 0 and R" 1 are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C7-cycloalkyl, C 3 -C 7 - WO 2005/123703 PCT/IB2005/002390 250 cycloalky-C-C 6 -alkyl, heteroaryl, C-C6-alkyl-heteroaryl, aryl, heterocycle; W' denotes a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0 and S, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from C, N, 0 and S, provided that W' is a aryl, heteroaryl or heterocycle selected from the group of formula: 0 GT G G-- N\ G4G% N G - N qN GGO N NN G1 N N Nj G4G4- 0 - ~ S G B B G q Gq- N - G - - G4 N G -- 51" N N G - G4 0 0 I N N i Y G/-HNG - G- -- G NN N OR12 O-3C7ccoakl 0-r0akl-eerl 0C N. N , 3q N Gq N+ q N 1N o 0 0~N ~ ~ -~ N. N1 7 1 Ga a GC- G3- C 7cy 'NN __ 01N ( NO Cqgropsylr ea3-cycloannlky1-Cse-lected frm-heeroaryl cositinofl hyroge,-alkyl-eey, aryl, 0-aryl, anrCtiallayl Csub -alkylhalo alky, Cr-C 6 -lyho 2 -C 6 -ny-RC-alknylC-ORC-C-alk ylS-R, O-akl OC-C 6 -akylS-Ro, C-C 6 -alcyl-S(=0-RC,-Cr -akyl, -S(=-Rly, 122z Co-CyalylC-(0)-aR, 0-C 7 -cyalkyl(=0)-Co-C alkyl- 1 NR 1 - ,0-r 6 -alkyl-N Rl -Ry, C-C 6 -lyyC 1 -C 6 --S(k)2NRR lo-C 121 hydroen, alogenR, CNOH, 6 lnyitr'o)a-opionll O-C 2 aedC-C 6 -lylS=-R, OC-C 6 -alkylS() 2 ', -C 1 -C 6 -alkyl-C-(=O) 2 -R 12 , -Co-C 6 -alkyl OR12 13-C-Ylakl 12IQakl-eeorl 13I-6 -C6-a-NR-S( ) 2 R 2, -CrC 6 -alkyl-S(=0) 2 NRR 3 , 0-CrC 6 -alkyl NR 2 -S(=0) 2 R'2, Co-C-alkyl-C(=)-NR' 2 R 3 , Co-CS-alkyl- WO 2005/123703 PCT/IB2005/002390 251 NRC(=O)-R", O-C-C 6 -alkyl-C(=0)-NR 12 RR", O-C 2 -C 6 -alkyl NR' 2 C(=O)-R, Co-C 6 -alkyl-OC(=O)-R, Co-C 6 -alkyl-C(=0)-OR, O-C 2 -C6-alkyl-OC(=O)-R', O-CI-C 6 -alkyl-C(=O)-OR , Co-C 6 -alkyl C(=O)-R' 2 , O-Cr-C 6 -alkyl-C(=O)-R 2 , Co-C 6 -alkyl-NR12-C(=O)-OR" , Co-C 6 -alkyl-O-C(=O)-NR1 2 R" or Co-C 6 -alkyl-NR'kC(=O)-NR"R'4 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, 0-CI-C 6 -alkyl, 0-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, 0-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C 1 -C 6 alkylaryl, C 3 -C 7 -Cycloalkyl, C 3 -C 7 -cycloalkyl-CI-C 6 -alkyl, 0-C 3 -C 7 cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5; R , R" and R1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted Cl-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; z 9 , ZI, z 11 , z1 2 , z 13 , Z1 4 , Z11, Z 16 and Z 17 are each independently selected from the group consisting of -C=, -C=C-, -C(=O)-, -C(=S)-, C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 Gq groups; 1 23 B , B and B3 are each selected independently from the group consisting of C, C=C, C=N, S, 0 or N which may further be substituted by one Gq group; Any N may be an N-oxide; provided that: when X is independently selected from NR 15 , 0, S or an optionally substituted CI-C 6 -alkyl, W is an optionally substituted 2-pyridinyl and Ri 5 is independently selected from hydrogen, an optionally substituted Ci-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C-C 7 cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, heteroaryl, Cr-C 6 -alkyl heteroaryl or aryl, W' can not be an optionally substituted aryl; when X is 0 and W' is an optionally substituted aryl or heteroaryl, W can not be an optionally substituted 3-pyridazinyl or 4-pyrimidinyl; when X is CH 2 and W' is aryl, W can not be 2-phenyloxazol-4-yl, 4 phenyloxazol-2-yl, 4-(3-(benzyloxy)propyl)-oxazol-2-yl, 4- WO 2005/123703 PCT/IB2005/002390 252 phenylthiazol-2-yl, 4-methylthiazol-2-yl or benzo[d]oxazol-2-yl, benzo[d]thiazol-2-yl; when X is 0 and W is an optionally substituted pyridinyl, W' can not be an optionally substituted 2-pyridinyl; when X is CH 2 CH 2 and W' is aryl, W can not be 4-imidazolyl. 3. A compound according to claim 2 having the formula II-A W Z9 Z1 '-z3 N"ZIS z- zIzi'iz (:D 11 \Z 11 _z 1 2 z 6 z _Z\1726 Gq II-A Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R2 R2 R 1 R2 R 3 -N R R2-<\ R3-<\ N- - R2N R R R 2 R2 I R N2 'xx> NSS R ' N -0 R RR 3 NN R R2 N R R 2 R 1 R 2 R 1 R 3 RN R 3 N R R R 2 R' R'x N Rd" N R3" N R3 ZN 3 R, R 2 , R2, R and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C 6 -alkyl, C1-C 6 -alkylhalo, C 2 -C 6 -alkcynyl, C 2 -C 6 alkenyl, 0-C 1 -C 6 -alkyl, 0-C 1 -C 6 -alkylhalo, 0-Cr-C 6 -alkynyl, 0-C 3 -C 6 - WO 2005/123703 PCT/IB2005/002390 253 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C 7 -cycloalkyl, O-C 1 -C 6 -alkyl heteroaryl, O-Cr-C6-alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 alkylaryl, CrC 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR 6 , C 3 -C 6 -alkenyl OR , Co-C 6 -alkyl-S-R 6, 0-C 2 -C 6 -alkyl-S-R6, Co-C 6 -alkyl-S(=O)-R , 0 C 2 -C 6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=0) 2 -R 6 , O-C-C 6 -alkyl-S(=0) 2 R6, Co-C 6 -alkyl-NR6RI, O-C 2 -C 6 -alkyl-NRR 7 , Co-C 6 -alkyl S(=0) 2 NR 6 R 7 , Co-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , O-C 1 -C 6 -alkyl S(=O) 2 NRR 7 , O-C1-C6-alkyl-NR 6 -S(=0) 2 R 7 , Co-C 6 -alkyl-C(=0) NR RI, Co-C 6 -alkyl-NR6 C(=O0)-R 7 , 0-C-C6-alkyl-C(=O)-NR6R', O C 2 -C 6 -alkyl-NR 6 C(=O)-R 7 , CoC6-alkyl-OC(=O)-R Co-C 6 -alkyl C(=O)-OR 6 , O-C 2 -C 6 -alkyl-OC(=O)-R 6 , 0-C 1 -C 6 -alkyl-C(=O)-OR 6 Co-C 6 -alkyl-C(=O)-R 6 , O-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 C(=O)-OR 7 , CC-C 6 -alkyl-O-C(=O)-NRR 7 or Co-C 6 -alkyl-NR 6 -C(=O) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-CI-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, 0-C-C6-alkyl-heteroaryl, O-C-C 6 alkylaryl, CI-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-CI-C 6 -alkyl, O-heteroaryl, heteroaryl, Cr C 6 -alkyl-heteroaryl, aryl, 0-aryl; Ri, R7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -a]kynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C6-alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z, Z 6 , Z7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted C-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, 0-C 3 -C 7 -cycloalkyl, C-C 6 -alkyl-O, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 0 -C 6 -akyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-O, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alki1-S(0)2, Co-C 6 -alkyl-NR 9 , Co-C 6 -NRS(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR , Co-C6-alkyl-C(=O)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), CO-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR 10 , Co-C 6 -alkyl-NR 9 -C(=NR' 0 )NRII, Co-C 6 -alkyl (C=NR 9 )NR" 0 , Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O)- WO 2005/123703 PCT/IB2005/002390 254 NR 9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C6-alkyl-O-N=CR 9 substituents; R9, R" and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalky-C 1 -C 6 -alkyl, heteroaryl, C1-C 6 -alkyl-heteroaryl, aryl, heterocycle; Z9, Zic, Zu, Z1, z1, Z, Z11, Z1 and Z7 are each independently selected from the group consisting of -C=, -C=C-, -C(=O)-, -C(=S)-, -C-, -0-, -N=, -N or -S- which may further be substituted by 1 to 5 G' groups; G" groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Ci-C 6 alkyl, C1-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C 1 -C 6 -alkyl, O-Ci-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR 12 , O-C-C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR1 2 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, Ci-C 6 -alkylhalo R12, 12, 12, 1_p 2 _ OR , C 3 -C 6 -alkynyl-OR , C 3 -C 6 -alkenyl-OR , Co-C 6 -alkyl-S-R , 0 1 12O- 1-lylS=)R 2 C 2 -C 6 -alkyl-S-R , Co-C,-alkyl-S(=0)-R 2 , 0-CrC,-alkyl-S(=0)-R Co-C 6 -alkyl-S(=0) 2 -R 2 , O-C-C 6 -alkyl-S(=0) 2 -R 2 , Co-C 6 -alkyl NR R", O-C 2 -C 6 -alkyl-NR 2 R 3 , Co-C 6 -alkyl-S(=0) 2 NR1 R", Co-C 6 alkyl-NR- 12 S(=) 2 R' 3 , O-C-C 6 -alkyl-S(=0) 2 NR' 2 R", O-C 2 -C 6 -alkyl NR 12 -S(=0) 2 R 13 Co-C 6 -alkyl-C(=O)-NR R", Co-C 6 -alkyl NR 2 C(=O)-R 1, O-C1-C 6 -alkyl-C(=O)-NR 12R 13, O-C 2 -C 6 -alkyl NR 2 C(=O)-R", Co-C 6 -alkyl-OC(=O)-R 12 , Co-C 6 -alkyl-C(=O)-OR12, O-C 2 -C 6 -alkyl-OC(=O)-R 2 , O-C-C 6 -alkyl-C(=O)-OR1 2 , Co-C 6 -alkyl C(=O)-R 12 , O-C-C 6 -alkyl-C(=O)-R 12 , Co-C 6 -alkyl-NR 2 -C(=O)-OR 3 , Co-C 6 -alkyl-O-C(=O)-NR 2 R 1 3 or Co-C 6 -alkyl-NR 1 2 -C(=O)-NR 13 R 14 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted Cl-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-CI-C 6 -alkyl, O-CI-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C 1 -C 6 alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, O-C 3 -C 7 cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, CI-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5; R ; R and R1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; WO 2005/123703 PCT/IB2005/002390 255 Any N may be an N-oxide. 4. A compound according to claim 3 having the formula II-Al w B_ CB 1 N II-Al Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: O R R' Rx R R 1 -~, - -R N0 N sI R2R2 R3RzR R R R 3-1 2 < R < R - < PNS N N s N N JR> N S N R 0 -N R'N- 0 R2N R 3 N R 2 N N ~ N/. Nj R 2 R1 R 2 R1 R R1 R 3 R'R' R2 2 2 N R R N R -~~N R R N ZV R2 R2 R 4 R 1 , R 2 , R3, Ri, Rs and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, ntro, an optionally substituted Cr-C 6 -alkyl, Cr-C 6 -alkcylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, 0-CrC 6 -alkyl, O-CrC 6 -alkylhalo, 0-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, 0-C 2 -C 6 -alkyl-OR, O-C 3 -C 7 -cycloalkyl, 0-Ci-C 6 -alkyl heteroaryl, 0-Cr-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-CrC 6 -alky1, O-C 3 -C 7 -cycloalkyl-CrC 6 -alkyl, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroarylH,aryl, 0-aryl, CrC 6 alkylaryl, Cr-C 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR 6 , C 3 -C 6 -alkenyl OR 6 , Co-C 6 -alkyl-S-R 6 , 0-C 2 -C-alkCyl-S-R 6 , Co-C 6 -alkyl-S(=0)-R 6 0 C 2 -C 6 -alkyl-S(=O)-R, Co-C 6 -alkyl-S(=O) 2 -R 6 , O-C-C 6 -alkyl-S(=0) 2 - WO 2005/123703 PCT/IB2005/002390 256 R6, Co-C 6 -alkyl-NR R', O-C 2 -C 6 -alkyl-NRR , Co-C 6 -alkyl S(=0) 2 NR 6 R 7 , Co-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , 0-C-C 6 -alkyl S(=0) 2 NR 6 R 7 , O-CI-C 6 -alkyl-NR 6 -_S(=0) 2 R 7 , Co-C 6 -alkyl-C(=0) NRR 7 , Co-C 6 -alkyl-NR 6 C(=O)-R 7 , O-C-C6-alkyl-C(=O)-NR 6 R 7 , 0 6 6 C 2 -C 6 -alkyl-NR6C(=O)-R 7 , Co-C 6 -alkyl-OC(=0)-R , Co-C 6 -alkyl C(=O)-OR 6 , O-C 2 -C 6 -alkyl-OC(=O)-R 6 , O-C-C 6 -alkyl-C(=O)-OR 6 , Co-C 6 -alkyl-C(0)-R 6 , 0-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 C(=0)-OR, Co-C 6 -alkyl-O-C(=0)-NR 6 R 7 or Co-C 6 -alkyl-R 6 -C(=O) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C 1 -C 6 -alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 alkenyl, 0-CI-C 6 -alkyl, 0-CI-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C3-C 7 -cycloalkyl, O-C-C6-alkyl-heteroaryl, O-C-C 6 alkylaryl, C-C 6 -alkylaryl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Cj-C 6 alkyl, 0-C3-C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C 1 C6-alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, CI-C 6 alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 -alkyl, heteroaryl, C-C6-alkyl-heteroaryl, aryl; ZI, Z2, Z ZI, 4 Z, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 Am groups; m is an integer from 1 to 5; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, 0-C -C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C3-C 7 -cycloalkyl, C-C 6 -alkyl-O, C 3 -C 7 -cycloalkyl, C3-C 7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, CI-C 6 alkylhalo-O, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6 -NR'S(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=0)-O, Co-C6-alkyl-O-C(=0)-NR, Co-C 6 alkyl-NR 9 -C(=O)-NR" 0 , Co-C 6 -alkyl-NR 9 -C(=NR 0 )NR'I, Co-C 6 -alkyl (C=NR 9 )NR ', Co-C 6 -alkyl-C(=0)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R 9 , R" 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C 1 -C 6 alkyihalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalky-C-C 6 -alkyl, heteroaryl, C-C6-alkyl-heteroaryl, aryl, heterocycle; WO 2005/123703 PCT/IB2005/002390 257 B and B 2 are each selected independently from N or C which may further be substituted by Gq groups; B3 is selected independently from C, C=C, C=N, S, 0 or N which may further be substituted by Gq groups; G4 groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Cr-C 6 alkyl, C-C6-alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR 12 , O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-Cr-C 6 alkylaryl, Co-C 6 -alkyl-OR1 2 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C,-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR' 2 , C 3 -C 6 -alkynyl-OR1 2 , C 3 -C 6 -alkenyl-OR 2 , Co-C 6 -alkyl-S-R 2 , O C 2 -C 6 -alkyl-S-R 2 , Co-C 6 -alkyl-S(=O)-R 2 , O-C 2 -C 6 -alkyl-S(=O)-R1 2 , Co-C 6 -alkyl-S(=0) 2 -R', O-Cr-C 6 -alkyl-S(=0) 2 -R 2 , Co-C 6 -alkyl NR12R13 O-C1-C 6 -alkyl-NR' 2 R1 3 , Co-C 6 -alkyl-S(=O) 2 NR1 2 R, 13 Co-C 6 alkyl-NR 12 -S(=0) 2 R1 3 , O-C-C 6 -alkyl-S(=O) 2 NR~R 1 3 , O-C 2 -C 6 -alkyl NR' 2 -S(=0) 2 R 3 , Co-C 6 -alkyl-C(=O)-NR1 2 R1 3 , Co-C 6 -alkyl NR 2 C(=O)-R 3 , O-C-C 6 -alkyl-C(=0)-NR R, O-C 2 -C 6 -alkyl NR C(=O)-R, Co-C6-alkyl-OC(=O)-R , Co-C 6 -alkyl-C(=O)-OR, O-C 2 -C 6 -alkyl-OC(=O)-R 2 , O-Cl-C 6 -alkyl-C(=O)-OR 2 , Co-C 6 -alkyl C(=O)-R' 2 , O-C-C 6 -alkyl-C(=O)-R 2 , Co-C 6 -alkyl-NR1 2 -C(=O)-OR, Co-C 6 -alkyl-O-C(=O)-NR1 R or CO-C 6 -alkyl-NR 2 -C(=O)-NR1R14 substituents; q is an integer from 1 to 5; 12 13 14 R , R and R are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, Cr-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C7-cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
5. A compound according to claim 3 having the formula I-A2 W N -Gq X-:x II-A2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein WO 2005/123703 PCT/IB2005/002390 258 W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R2 R2 O R 3 -N RRR RRR El1 2 3l ~ - l ~ R3+R2-N R2R< R 2 N E 3 R N N N~A Ni~ R 2 2R 2 RR R 3 R' 3 R R3 N R' R 2 'NR 2Y N NX El 4 N N / /R < N / l 3 NV N-0 R R1 R N RE 2 R2 R A R N - N R3 N RNmz N R, R 2 ,R 3 , R 4 , R and Am are each independently selected from the group consisting of hydrogen, halogen, CN, 0OH, ntro, an optionally substituted Ci-C 6 -alkyl, Ci-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-Cr-C 6 -alkyl, 0-Cr-C 6 -alkylhalo, 0-C 3 -C 6 -alkyny1, 0-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR O-C 3 -C 7 -cycloalkyl, O-CZC 6 -alkyl heteroaryl, 0-Ci-C 6 -alkylaryl, Co-Ch-alkyl-OR, C3-C 7 -eycloalkyl, C 3 C7-cycloalkyl-C 1 -C 6 -alkyl, O-C3-C7-cycloalkyl-C1-C 6 -alkyl, 0 heteroaryl, heteroaryl, CrC6-alkyl-heteroaryl, aryl, O-aryl, C3-C 6 alkylaryl, Cr-C 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR 6 , C3-C 6 -alkenyl OR 6 , Co-C 6 -alkyl-S-R 6 , 0-C 2 -C 6 -alkyl-S-R 6 , Co-C 6 -alkyl-S(=0)-R 6 , 0 C 2 -C 6 -alkyl-S(=0)-R 6 , Co-C 6 -alkyl-S(=0) 2 -R 6 , O-C1-C 6 -alkyl-S(=0) 2 R, Co-C-alkyl-NRR, O-C 2 -C 6 -alkyl-NR 6 R 7 , Co-CS-alkyl S(=0) 2 NR 6 R', Co-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , 0-C-C6-alkyl S(=O) 2 NR 6 R 7 , O-C1-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , Co-C 6 -alkyl-C(=O) NR R7, Co-C 6 -alkyl-NR 6 C(=O)-R 7 , O-C-C 6 -alkyl-C(=O)-NR 6 R 7 , 0 C 2 -C 6 -alkyl-NR 6 C(=O)-R 7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl C(=O)-OR 6 , O-C 2 -C 6 -alkyl-OC(=O)-R',- O-CI-C 6 -alkyl-C(=O)-OR 6 Co-C 6 -alkyl-C(=O)-R 6 , O-CI-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR 6 R7 or Co-C 6 -alkyl-NR 6 -C(=O) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C3-C 6 -allkynyl, O-C 3 -C 6 - WO 2005/123703 PCT/IB2005/002390 259 alkenyl, O-C3-C 7 -cycloalkyl, O-Ci-C6-alkyl-heteroaryl, 0-CI-C 6 alkylaryl, C1-C 6 -alkylaryl, C3-C 7 -cycloalkyl, C3-C7-cycloalkyl-C1-C 6 alkyl, 0-C3-C 7 -cycloalkyl-C 1 -C 6 -alkyl, 0-heteroaryl, heteroaryl, C C6-alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C 6 -alkyl, C1-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C1-C 6 -alkyl, heteroaryl, C1-C6-alkyl-heteroaryl, aryl; 1 23 z , z , Z3, Z 4 , Z, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted C1-C 6 -alkyl, CI-C-alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C-alkyl, O-C1-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C3-C 6 -alkenyl, O-C3-C 7 -cycloalkyl, C 1 -C 6 -alkyl-O, C3-C 7 -cycloalkyl, C3-C7-cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, Cr-C 6 alkylhalo-O, C3-C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=O) 2 , CC-C 6 -alkyl-NR 9 , Co-C 6 -NR 9 S(=O) 2 , Co-C 6 -a1kyl-S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=0)-NR 9 , Co-C 6 -alkyl N 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR' 0 , Co-C 6 -alkyl-NR 9 -C(=NR 10 )NR", Co-C 6 -alkyl (C=NR 9 )NR' , Co-C6-alkyl-C(=O)-O-C-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R', R' 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C 6 -alkyl, C1-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C 3 -C 7 cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; G4 groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Cl-C 6 -alkyl, 0-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR' 2 O-C3-C 7 -cycloalkyl, O-C,-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Co-C 6 -alkyl-OR , C3-C 7 -cycloalkyl, C3-C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR' 2 , C 3 -C 6 -alkynyl-OR1 2 , C3-C 6 -alkenyl-OR 2 , Co-C 6 -alkyl-S-R 2 , 0 C 2 -C,-alkyl-S-R 2 , Co-C 6 -alkyl-S(=O)-R1 2 , O-C 2 -C 6 -alkyl-S(=O)-R1 2 , Co-C 6 -alkyl-S(=0) 2 -R 2 , O-Cl-C6-alkyl-S(=0) 2 -R1 2 , Co-C 6 -alkyl NRR", O-C 2 -C 6 -alkyl-NR 1 2 R1 3 , Co-C 6 -alkyl-S(=0)2NR1 2 R", Co-C 6 alkyl-NR'-S( 0) 2 R1 3 , O-C-C 6 -alkyl-S(=0) 2 NR' 2 R 3, O-C2-C 6 -alkyl NR-S(=0)2R , Co-C 6 -alkyl-C(=0)-NR1 2 R 3 , Co-C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 260 NR 1 C(=O)-R, O-Cl-C 6 -alkyl-C(=O)-NR 12 R' 3 , -C 2 -C 6 -alll NR C(=0)-R", Co-C 6 -alkyl-OC(=O)-R , CO-C 6 -alkyl-C(=0)-OR 2 O-C2-C6-alkyl-OC(=O)-R 12 , 0-CIC6-alkyl-C(=0)-OR", Co-C 6 -alkyl C(=0)-R 1, 0)-CrC,-alkyl-C(=0))-R 1, Co-C6-al-ky1_NR12-C(=0)-OP 13, Co-C 6 -alkyl-O-C(=O)-NR 2 R 1 3 or Co-C6-alky1NR1 2 -C(=O)-NR 3 R" substituents; q is an integer from 1 to 5; R , R and R1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C-C 6 alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-Cl-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
6. A compound according to claim 5 having the formula II-A2-a R2 R 1 R 3 N _ N R4 N X - G q II-A2-a Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R', R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1 -C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 -alkyl, O-Cm-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR 5 , O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-CI-C 6 -alkyl, 0 C 3 -C 7 -cycloalkyl-C-C 6 -alky1, 0-heteroaryl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl, O-aryl, C-C6-alkylaryl, C-C6-alkylhalo-OR, C 3 -C 6 alkynyl-OR 5 , C 3 -C 6 -alkenyl-OR, CC-C 6 -alkyl-S-R 5 , O-C 2 -C 6 -alkyl-S R5, Co-C 6 -alkyl-S(=O)-R', O-C 2 -C 6 -alkyl-S(=O)-R 5 , Co-C 6 -alkyl S(=0) 2 -R 5 , O-C-C 6 -alkyl-S(=O) 2 -R, Co-C 6 -alkRyl-NR6, O-C 2 -C 6 alkyl-NR R, Co-C 6 -alkyl-S(=0) 2 NR5R 6 , Co-C 6 -alkyl-NR 5 -S(=O) 2 R', O-C-C 6 -alkyl-S(=O) 2 NRsR, O-C 2 -C 6 -alkyl-NRs-S(=0) 2 R 6 , Co-C 6 alkyl-C(=O)-NRR', Co-C 6 -alkyl-NR 5 C(=O)-R 6 , 0-CI-C 6 -alkyl C(=O)-NRR 6 , O-C 2 -C 6 -alkyl-NR 5 C(=O)-R , Co-C 6 -alkyl-OC(=O)-R 5 , Co-C 6 -alkyl-C(=O)-ORs, O-C 2 -C 6 -alkyl-OC(=O)-R 5 , 0-CI-C 6 -alkyl C(=O)-OR, Co-C 6 -alkyl-C(=O)-R, O-CI-C 6 -alky1-C(=0)-R 5 , Co-C 6 - WO 2005/123703 PCT/IB2005/002390 261 alkyl-NRs-C(=O)-0R 6 , Co-C 6 -alkyl-O-C(=0)-NRR 6 or Co-C 6 -alkyl NR 5 -C(=O)-NR 6 R 7 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted Cl-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C6-alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-C,-C 6 -alkylhalo, O-C 3 -C6-alkynyl, O-C 3 -C 6 alkenyl, O-C3-C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Cr-C 6 -alkylaryl, C-C 7 -cycloalkyl, C3-C 7 -cycloalkyl-Cr-C 6 alkyl, O-C3-C 7 -cycloalkyl-Cj-C 6 -alkyl, 0-heteroaryl, heteroaryl, C 1 C6-alkyl-heteroaryl, aryl, O-aryl; R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C6-alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 -cycloalkyl, C-C 6 -alkyl-O, C3-C 7 -cycloalkyl, C3-C 7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-O, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C6-alkyl-S(=O) 2 , Co-C 6 -alkyl-NR 8 , Co-C 6 -NR 8 S(=0) 2 , Co-C 6 -alkyl-S(=O) 2 NR 8 , Co-C 6 -alkyl-C(=O)-NR 8 , Co-C 6 -alkyl NR 8 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 8 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR, Co-C 6 alkyl-NR 8 -C(=O)-NR 9 , Co-C 6 -alkyl-NRs-C(=NR 9 )NR" , Co-C 6 -alkyl (C=NR 8 )NR', Co-C6-alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C6-alkyl-C(=O) NR8-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 8 ) or Co-C6-alkyl-O-N=CR8 substituents; R 8 , R 9 and R1 0 are each independently selected from the group consisting of hydrogen, an optionally substituted C,-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalky-Cr-C 6 -alkyl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-CI-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C3-C 6 -alkynyl, O-C-C 6 -alkenyl, O-C2-C 6 -alkyl OR", O-C 3 -C 7 -cycloalkyl, O-C-C6-alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR", C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Cl C 6 -alkyl, 0-C 3 -C 7 -cycloalkyl-Cr-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C6-alkyl-heteroaryl, aryl, 0-aryl, C-C6-alkylaryl, C-C 6 -alkylhalo OR", C 3 -C 6 -alkynyl-OR", C 3 -C 6 -alkenyl-OR", Co-C 6 -alkyl-S-R", 0 C 2 C 6 -alkyl-S-R", Co-C 6 -alkyl-S(=O)-R", O-C 2 -C 6 -alkyl-S(=O)-R", Co-C 6 -alkyl-S(=O) 2 -R'1, O-C-C 6 -alkyl-S(=O) 2 -R, Co-C 6 -alkyl NR"R1 2 , O-C 2 -C-alkyl-NR"R1 2 , Co-C 6 -alkyl-S(=0) 2 NR"R1 2 , Co-C 6 alkyl-NR"-S(=0) 2 R 2 , O-C-C 6 -alkyl-S(=0) 2 NR"R 2 , O-C 2 -C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 262 NR'-S(=0) 2 R 2 , Co-C 6 -alkyl-C(=O)-NR"R 1 2 , Co-C 6 -alkyl NR"C(=O)-R1 2 , O-C-C 6 -alkyl-C(=O)-NR" R, O-C 2 -C 6 -alkyl NR"C(=O)-R , Co-C-alkyl-OC(=O)-R", Co-C 6 -alkyl-C(=O)-OR", O-C 2 -C 6 -alkyl-OC(=O)-R", 0-C-C 6 -alkyl-C(=O)-OR", Co-C 6 -alkyl C(=O)-R, O-C-C 6 -alkyl-C(=O)-R", Co-C 6 -alkyl-NR 11 -C(=O)-OR 1, Co-C6-alkyl-O-C(=O)-NRuR 2 or Co-C 6 -alkyl-NR' -C(=O)-NR R substituents; q is an integer from 1 to 5; R", R1 2 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkyihalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
7. A compound according to claim 6 having the formula II-A2-al R2 R' R N II-A2-al Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R', R 2 , R3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, CN, OH, an optionally substituted Cr-C 6 -alkyl, C C 6 -alkylhalo, Co-C 6 -alkyl-NR 5 R 6 , Co-C 6 -alkyl-S(=0) 2 NRR 6 , Co-C 6 alkyl-NRs-S(=0) 2 R 6 , Co-C 6 -alkyl-C(=O)-NRR 6 , Co-C 6 -alkyl NR 5 C(=O)-R 6 , Co-C 6 -alkyl-OC(=O)-Rs, Co-C 6 -alkyl-C(=O)-OR, Co C 6 -alkyl-CQ=O)-R 5 or Co-C 6 -alkyl-NR 5 -C(=O)-NRR 7 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C3-C6-alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C 1 -C 6 alkylaryl, C-C6-alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkcyi-C-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, 0-aryl; WO 2005/123703 PCT/IB2005/002390 263 wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, Cj-C 6 -alkylhalo, C2-C6-alkynyl, C 2 -C 6 alkenyl, O-Cl-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C6-alkynyl, O-C3-C6 alkenyl, O-C3-C 7 -cycloalky1, O-CrC-alkyl-heteroaryl, O-C-C 6 alkylaryl, Cl-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 6 alkyl, O-C3-C7-cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C6-alkyl-heteroaryl, aryl, 0-aryl; Rs, R6 and RJ are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C3-C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, heteroaryl, CIC 6 -alkyl-heteroaryl, aryl; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, O-Co-C 6 -alkyl, Co-C 6 -alkyl-O, S-Co-C 6 -alkyl, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 8 , Co-C 6 -NRSS(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR', Co-C 6 -alkyl-C(=O)-NR 8 , Co-C 6 -alkyl NR 8 C(=O), Co-C 6 -alkyl-C(=0)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 8 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) or Co-C 6 -alkyl-NR 8 -C(=O)-NR 9 substituents; R8 and R are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, Cl-C 6 -alkylhalo, C2 C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalky-C-C 6 alkyl, heteroaryl, Cr1C6-alkyl-heteroaryl, aryl; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1 -C 6 alkyl, C-C 6 -alkylhalo, O-C 1 -C 6 -alkyl, O-Ci-C 6 -alkylhalo, O-C 2 -C 6 alkyl-ORU, O-C3-C 7 -cycloalkyl, O-C-C6-alkyl-heteroaryl, O-CI-C 6 alkylaryl, Co-C 6 -alkyl-OR'o, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C 1 -C 6 -alkylaryl, CI-C 6 -alkylhalo OR", Co-C 6 -alkyl-S(=O)-R 0 , O-C 2 -C 6 -alkyl-S(=O)-R' 0 , Co-C 6 -alkyl S(=0) 2 -R' 0 , O-C-C 6 -alkyl-S(=0) 2 -R', Co-C 6 -alkyl-NR 0 R", O-C 2 -C 6 alkyl-NR 0 R 11 , Co-C 6 -alkyl-S(=0) 2 NR 10 R", Co-C 6 -alkyl-NR 1 0 S(=0) 2 R", O-C1-C 6 -alkyl-S(=O) 2 NR 0 R1, O-C 2 -C6-alkyl-NR' 0 S(=0) 2 R", Co-C 6 -alkyl-C(=O)-NRIR 1 , C-C-alkyl-NR1 0 C(=O)-R", 0-CrCO-alkyl-C(=0)-NR1'R", 0-C 2 -C 6 -alkyl-NR' 0 C(=O)-R', Co-C 6 alkyl-C(=O)-Rl 0 , O-C-C 6 -alkyl-C(=O)-R' 0 or Co-C,-alkyl-NR1' 0 C(=O)-NR 'R 12 substituents; q is an integer from 1 to 5; R 10 , R' 1 and R 12 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, CI-C 6 - WO 2005/123703 PCT/IB2005/002390 264 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-CI-C6-alkyl, heteroaryl, C-C6-alkyl-heteroaryl, aryl; Any N may be an N-oxide.
8. A compound according to claim 7 having the formula II-A2-a2 R2 RI N -Gq R 4 N II-A2-a2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R1, R2, R and R are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted CI-C 6 -alkyl, CI-C 6 alkylhalo or Co-C 6 -alkyl-NR 5 R 6 substituents; Rs and R6 are each independently selected from the group consisting of hydrogen, an optionally substituted Cl-C 6 -alkyl, Ci-C 6 -alkylhalo, C3 C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Cj-C 6 -alkyl, heteroaryl, CI-C 6 -alkyl heteroaryl, aryl; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, an optionally substituted Ci-C 6 -alkyl, Cr-C 6 alkylhalo, O-Co-C 6 -alkyl, O-Co-C 6 -alkylaryl, heteroaryl or aryl; q is an integer from 1 to 5; Any N may be an N-oxide.
9. A compound according to claim 3 having the formula II-A3 wB N'B II-A3 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound WO 2005/123703 PCT/IB2005/002390 265 Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R2 R R 3 -N R R2 R RN R N x N s RN R R2N R 3 RR 3 R N N R 2 R 1 22 R 1 R 3 R1 R3 Ri R'2 R2\ Z3Z N R I'N N 'N. z N~r~ N A' 1 R4NNR N R3 ~Irl R1Nr R2 R2 R1 R3 2R3 4 52Z R, R, R, R, R and A m are each independently selected the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C6-alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 alkenyl, O-CI-C 6 -alkyl, O-CI-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl heteroaryl, O-CI-C 6 -alkylaryl, Co-C 6 -alkyl-OR6, C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-Cl-C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0 heteroaryl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C 1 -C 6 alkylaryl, CI-C 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR 6 , C 3 -C 6 -alkenyl OR , Co-C 6 -alkyl-S-R , O-C 2 -C 6 -alkyl-S-R6, Co-C 6 -alkyl-S(=O)-R6, 0 C 2 -C 6 -alkyl-S(=O)-R 6 , Co-C6-alkyl-S(=0) 2 -R 6 , O-C-C 6 -alkyl-S(=O) 2 R6, Co-C 6 -alkyl-NR 6 R 7 , O-C 2 -C 6 -alkyl-NR 6 R 7 , Co-C6-alkyl S(=0) 2 NR 6 R 7 , Co-C 6 -alkyl-NR-S(=0) 2 R 7 , O-CI-C6-alkyl S(=0) 2 NRR 7 , O-C-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , Co-C6-alkyl-C(=O) NR R, Co-C 6 -alkyl-NR 6 C(=0)-R 7 , 0 C 2 -C 6 -alkyl-NR 6 C(=O)-R 7 , Co-C 6 -alkyl-OC(=O)-R, Co-C 6 -alkyl C(=O)-OR 6 , O-C 2 -C6-alkyl-OC(=O)-R 6 , O-C-C6-alkyl-C(=O)-OR 6 , Co-C 6 -alkyl-C(=O)-R 6 , O-C 1 -C 6 -alkyl-C(=O)-R, Co-C 6 -alkyl-NR C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR 6 R7 or Co-C 6 -alkyl-NR 6 -C(=O) NR R substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CIC6-alkyl, C-C6-alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 - WO 2005/123703 PCT/IB2005/002390 266 alkenyl, O-Cr-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C3-C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-Cl-C6-alkyl-heteroaryl, 0-Cr-C 6 alkylaryl, C-C6-alkylaryl, C-C 7 -cycloalkyl, C-C 7 -cycloalkyl-CI-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-Cj-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, 0-aryl; R 6 , R7 and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C-C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C,-C6-alkyl-heteroaryl, aryl; Z1, Z2, Z3, Z 4 , ZI, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted Cr-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkyny1, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0 C 3 -C 6 -alkyny1, O-C 3 -C 6 -alkenyl, O-C3-C 7 -cycloalkyl, Co-C 6 -alkyl-O, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-0, C 3 -C 6 -alkynyl-O, C-C 6 -alkenyl-0, Co-C-alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=O) 2 , Co-C 6 -alkyl-NR?, Co-C 6 -NR 9 S(=O) 2 , Co-C 6 -alkyl-S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=0), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR 0 , Co-C 6 -alkyl-NR 9 -C(=NR' 0 )NR , Co-C 6 -alkyl (C=NR 9 )NR ', Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 sub stituents; RI, R 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C-C 7 -cycloalkyl, C 3 -C 7 cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; B1 represents independently C or N which may further be substituted by GI groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C-C 6 -alkenyl, O-C 2 -C 6 -alkyl OR1 2 , O-C-C 7 -cycloalkyl, O-C,-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR1 2 , C-C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Cl C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C,-C 6 -alk.ylhalo OR 12, C 3 -C 6 -alkynyl-OR , C 3 -C 6 -alkenyl-OR 2 , Co-C 6 -alkyl-S-R 12, 0_ C 2 -C 6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R , O-C 2 -C 6 -alkyl-S(=O)-R, WO 2005/123703 PCT/IB2005/002390 267 Co-C 6 -alkyl-S(=0) 2 -R 12 , 0-CI-C 6 -alkyl-S(=O) 2 -R 2 , Co-C 6 -alkyl NR12R", O-C 2 -C 6 -alkyl-NRR", Co-C 6 -alkyl-S(=O) 2 NR 2 R", Co-C 6 alkyl-NR1 2 -S(=0) 2 R", O-C-C 6 -alkyl-S(=0) 2 NRR 12 R", O-C 2 -C 6 -alkyl NR12_S(0)2R 1 CO-C6-lkylC=O)_N12 13 OC6akl NR 2 -S(=O) 2 R 13 , Co-C 6 -alkyl-C(=O)-NR R , Co-C 6 -alkyl NR 2 C(=0)-R 13 , Co-C 6 -alkyl-OC(=O)-R 12 , Co-C6-alkyl-C(=O)-OR1 2 , O-C 2 -C 6 -alkyl-OC(=O)-R", O-C-C 6 -alkyl-C(=O)-OR 2 , Co-C 6 -alkyl C(=O)-R 12 , O-C-C 6 -alkyl-C(=O)-R 12 , Co-C 6 -alky1lR1 2 -C(=O)-OR, Co-C 6 -alkyl-O-C(=O)-NRR" or Co-C 6 -alkyl-NR 1 2 -C(=O)-NR1 3 R4 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 alkyl, O-CI-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-CI-C 6 -alkylaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5; R , R and R" are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
10. A compound according to claim 9 having the formula II-A3-a R2 RB R2 - / . N' Gq R R4 ~-- N:G II-A3-a Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R', R2, R? and R4 are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 -alkyl, O-CI-C 6 -alkylhalo, O-C3-C 6 -alkynyl, O-C3-C 6 -alkenyl, O-C 2 -C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 268 OR 5 , O-C 3 -C 7 -cycloalkyl, O-Ci-C 6 -alkyl-heteroaryl, 0-C 1 -C 6 -alkylaryl, Co-C 6 -alkyl-OR 5 , C3-C 7 -cycloalkyl, C3-C7-cycloalkyl-Ci-C 6 -alkyl, 0 C3-C7-cycloalkyl-C1-C 6 -alkyl, 0-heteroaryl, heteroaryl, Ci-C 6 -alkyl heteroaryl, aryl, O-aryl, CI-C 6 -alkylaryl, Ci-C 6 -alkylhalo-OR 5 , C 3 -C 6 alkynyl-OR 5 , C3-C6-alkenyl-OR, Co-C 6 -alkyl-S-R, O-C 2 -C 6 -alkyl-S R5, Co-C6-alkyl-S(=0)-R, O-C 2 -C 6 -alkyl-S(=O)-R 5 , Co-C 6 -alkyl S(=0) 2 -R 5 , O-CI-C 6 -alkyl-S(=0) 2 -R 5 , Co-C 6 -alkyl-NR 5 R, O-C 2 -C 6 alkyl-NRR 6 , Co-C 6 -alkyl-S(=0) 2 NR 5 R , Co-C 6 -alkyl-Nk 5 -S(=0) 2 R 6 , O-CI-C6-alkyl-S(=0) 2 NRR 6 , O-C 2 -C 6 -alkyl-NR -S(=0) 2 R 6 , Co-C 6 alkyl-C(=O)-NRR, Co-C 6 -alkyl-NR 5 C(=O)-R', O-C1-C 6 -alkyl C(=O)-NRR 6 , O-C2-C 6 -alkyl-NRsC(=O)-R 6 , Co-C 6 -alkyl-OC(=O)-R, Co-C6-alkyl-C(=0)-OR5, O-C 2 -C 6 -alkyl-OC(=O)-R', O-C1-C 6 -alkyl C(=O)-OR 5 , Co-C 6 -alkyl-C(=O)-R 5 , O-Ci-C 6 -alkyl-C(=O)-R, Co-C 6 alkyl-NR 5 -C(=0)-OR, Co-C 6 -alkyl-O-C(=O)-NRR 6 or Co-C 6 -alkyl NR 5 -C(=O)-NR R7 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, C1-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C1-C 6 -alkyl, O-Ci-C 6 -alkylhalo, 0-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalky1, O-C1-C6-alkyl-heteroaryl, O-CI-C 6 alkylaryl, CI-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C3-C 7 -cycloalkyl-C 1 -C 6 alkyl, O-C3-C 7 -cycloalkyl-C1-C 6 -alkyl, 0-heteroaryl, heteroaryl, C 1 C6-alkyl-heteroaryl, aryl, 0-aryl; R5, R6 and R7 are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C 6 -alkyl, C 1 -C 6 alkylhalo, C2-C6-alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 -alkyl, heteroaryl, Ci-C6-alkyl-heteroaryl, aryl; X is selected from an optionally substituted Ci-C 6 -alkyl, C 1 -C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-Ci-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 -cycloalkyl, Co-C 6 -alkyl-O, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C 1 -C 6 alkylhalo-O, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 8 , Co-C 6 -NR 8 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR', Co-C 6 -alkyl-C(=O)-NR 8 , Co-C6-alkyl NR8 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=0), Co-C 6 -alkyl-NR 8 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR', CO-C 6 alkyl-NR-C(=O)-NR 9 , Co-C 6 -alkyl-NRS-C(=NR)NRO, Co-C 6 -alkyl (C=NR)NR', Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 8 -CO-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 8 ) or Co-C 6 -alkyl-O-N=CR substituents; R', R 9 and RO are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalky-C 1 -C 6 -alkyl, heteroaryl, Ci-C-alkyl-heteroaryl, aryl; WO 2005/123703 PCT/IB2005/002390 269 BI represent independently C or N which may further be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Cr-C 6 alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Cr-C 6 -alkyl, O-C,-C 6 -alkylhalo, O-C3-C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR", O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Co-C 6 -alkyl-OR", C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, 0-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, 0-aryl, Cr-C 6 -alkylaryl, C-C 6 -alkylhalo OR", C 3 -C 6 -alkynyl-OR", Cr-C 6 -alkenyl-OR", Co-C,-alkyl-S-R", 0 C 2 -C 6 -alkyl-S-R", Co-C 6 -alkyl-S(=O)-R1, O-C 2 -C 6 -alkyl-S(=O)-R", Co-C 6 -alkyl-S(=O) 2 -R", O-C-C 6 -alkyl-S(=O) 2 -R", Co-C 6 -alkyl NR"R 2 , O-C 2 -C 6 -alkyl-N''R' 2 , Co-C 6 -alkyl-S(=O) 2 NR"R 2 , Co-C 6 alkyl-NR'-S(=O) 2 R1 2 , O-C-C 6 -alkyl-S(=0) 2 NR"R1 2 , O-C 2 -C 6 -alkyl NR 1 -S(=0) 2 R 2 , Co-C 6 -alkyl-C(=O)-NR"R 2 , Co-C 6 -alkyl NR C(=O)-R , O-C-C 6 -alkyl-C(=O)-NR 11 R1 2 , O-C 2 -C 6 -alkyl NR 1 C(=0)-R", Co-C 6 -alkyl-OC(=O)-R1, Co-C 6 -alkyl-C(=O)-OR", O-C 2 -C 6 -alkyl-OC(=O)-R 1 , O-C-C 6 -alkyl-C(=O)-OR", Co-C 6 -alkyl C(=0)-R", O-CI-C 6 -alkyl-C(=O)-R'1, Co-C 6 -alkyl-NR'"-C(=O)-OR1', Co-C 6 -alkyl-O-C(=O)-NR'"R 1 2 or Co-C 6 -alkyl-NR' 1-C(=O)-NR 2 R1 3 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 -alkylaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, O-C3-C 7 -cycloalkyl-C-C 6 alkyl, 0-heteroaryl, heteroaryl, Cl-C6-alkyl-heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5; R", R1 2 and R1 3 are each independently selected from the group consisting of hydrogen, an optionally substituted Cl-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Cl-C6-alkyl-heteroaryl, aryl; Any N may be an N-oxide.
11. A compound according to claim 10 having the formula II-A3-al WO 2005/123703 PCT/IB2005/002390 270 R 2 R' -N X- N -- Gq II-A3-al Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R', R 2 , R 3 and R4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, Co-C 6 -alkyl-ORs, Co-C 6 -alkyl-NRR 6 , Co-C 6 -alkyl NRC(=O)-R or Co-C 6 -alkyl-NR 5 S(=0) 2 -R 6 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, Cl-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-CIC 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C6-alkyl-heteroaryl, O-C-C 6 alkylaryl, Cl-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C6-alkyl-heteroaryl, aryl, 0-aryl; R5 and R6 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 3 C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Cr-C 6 -alkyl, heteroaryl, Ci-C 6 -alkyl heteroaryl, aryl; X is selected from an optionally substituted C-C 6 -alkyl and C-C 6 alkylhalo; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C 1 -C 6 alkyl, C-C 6 -alkylhalo, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 2 -C 6 alkyl-OR 7 , O-C 3 -C 7 -cycloalkyl, O-Ci-C 6 -alkyl-heteroaryl, 0-Cr-C 6 alkylaryl, Co-C 6 -alkyl-0R 7 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, O-aryl, Ci-C 6 -alkylaryl, C-C 6 -alkylhalo OR7, Co-C 6 -alkyl-S(=O)-R 7 , O-C 2 -C 6 -alkyl-S(=O)-R 7 , Co-C 6 -alkyl S(=0) 2 -R 7 , O-C-C 6 -alkyl-S(=0) 2 -R 7 , Co-C,-alkyl-NR 7 R', O-C 2 -C 6 alkyl-NR 7 R', Co-C 6 -alkyl-S(=0) 2 NR7R', Co-C 6 -alkyl-NR 7 -S(=0) 2 R 8 , O-C-C 6 -alkyl-S(=0) 2 NR 7 R, O-C 2 -C 6 -alkyl-NR -S(=0) 2 R 8 , Co-C 6 alkyl-C(=O)-NR7R, Co-C 6 -alkyl-NR 7 C(=O)-R, O-C-C 6 -alkyl C(=O)-NR 7 R', O-C 2 -C 6 -alkyl-NR 7 C(=O)-R, Co-C 6 -alkyl-C(=O)-R 7 , WO 2005/123703 PCT/IB2005/002390 271 O-CI-C 6 -alkyl-C(=0)-R7 or Co-C 6 -alkyl-NR 7 -C(=O)-NR R9 substituents; q is an integer from 1 to 4; R7, R and R are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, Ci-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C-alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-Ci-C 6 -alkyl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
12. A compound according to claim 11 having the formula I-A3-a2 R2 R 1 R3 NN N N N II-A3-a2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein R1, R2, R3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 alkyllialo, Co-C 6 -alkyl-OR 5 , Co-C 6 -alkyl-NRSR 6 , Co-C-alkyl NRC(=O)-R6 or Co-C 6 -alkyl-NRiS(=O) 2 -R' substituents; R5 and R 6 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C1-C 6 -alkylhalo, C 3 C 7 -cycloalkyl, heteroaryl, aryl; C q groups are each independently selected from the group consisting of hydrogen, halogen, nitro, CN, an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo, O-Co-C6-alCyl, O-Co-C6-alkylaryl, heteroaryl, aryl or Co-C-alkyl-NRR 8 substituents; q is an integer from 1 to 4; R 7 and R' are each independently selected from the group consisting of hydrogen, an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo, heteroaryl, aryl; Any N may be an N-oxide. WO 2005/123703 PCT/IB2005/002390 272
13. A compound according to claim 3 having the formula II-A4 (DW- == X B2 _Gq N-G ~B II-A4 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R2 R 2 R 2 R1 R2 RR2 2 R SR 3 N R 2- NN R + < I:/I- 1 />~? R2 N, R, / R1</' 2N N N-J/ R 2 R 1 R 2 R 1 R R 3 R 3 R1 Z.ZRN2 R, R 2 , R 3 , R 4 , R and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted Cr-C 6 -alky1, Cr-C 6 -alkcylhalo, C 2 -C 6 -alkyny1, C 2 -C 6 alkenyl, 0-Cr-C 6 -alkyl, 0-Ci-C 6 -alkylhalo, O-C3-C 6 -alkynyl, 0-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C 7 -cycloalkyl, 0-Cr-C 6 -alkyl heteroaryl, O-Cr-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkcyl-Cr-C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, 0 heteroaryl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, 0-aryl, Cr-C 6 alkylaryl, Cr-C 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR 6 , C 3 -C 6 -alkenyl OR , Co-C 6 -alkyl-S-R4, O-C 2 -C 6 -alkyl-S-R6, Co-C 6 -alkyl-S(=0)-R 6 , 0 C 2 -C 6 -alkyl-S(=0)-R6, Co-C 6 -alkyl-S(=0) 2 -R6, 0-Cr-C 6 -alkyl-S(=0) 2 6 671 R, Co-C 6 -alkyl-NR R, 0-C 2 -C 6 -alky-NR 6 R 7 , Co-C 6 -alkyl S(--0) 2 NRiR 7 , Co-C 6 -alkyl- 6 -S(=o) 2 R 7 , O-CI-C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 273 S(=0) 2 NR 6 R 7 , O-CI-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , Co-C 6 -alkyl-C(=O) NR 6 R 7 , Co-C 6 -alkyl-NR 6 C(=O)-R 7 , O-Cr-C 6 -alkyl-C(=O)-NRR 7 , 0 C2-C 6 -alkyl-NR 6 C(=0)-R 7 , Co-C 6 -alkyl-OC(=0)-R 6 , Co-C 6 -alkyl 66 C(=0)-OR 6 , 0-C 2 -C 6 -alkyl-OC(=0)-R, O-CI-C 6 -alkyl-C(=0)-OR 6 , Co-C 6 -alkyl-C(=O)-R 6 , 0-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 _ C(=0)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR 6 R 7 or Co-C 6 -alkyl-NR 6 -C(=0) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, Ci-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-CI-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C3-C6-alkynyl, O-C 3 -C 6 alkenyl, O-C3-C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, CI-C 6 -alkylaryl, C3-C 7 -cycloalkyl, C3-C 7 -cycloalkyl-C-C 6 alkyl, 0-C3-C 7 -cycloalkyl-Cr-C 6 -alkyl, O-heteroaryl, heteroaryl, C C6-alkyl-heteroaryl, aryl, 0-aryl; 6 78 R, R7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted Cr-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, Ci-C6-alkyl-heteroaryl, aryl; Z1, Z2, Z , Z4, Z5, Z6, Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 Am groups; m is an integer from 1 to 5; X is selected from an optionally substituted CI-C 6 -alkyl, CI-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 -cycloalkyl, Co-C 6 -alkyl-O, C3-C 7 -cycloalkyl, C3-C7-cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, C 1 -C 6 alkylhalo-0, C 3 -C 6 -alkynyl-0, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=O)2, Co-C 6 -alkyl-NR 9 , Co-C 6 -NR 9 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR, Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR' 0 , Co-C 6 -alkyl-NR 9 -C(=NR')NR", Co-C 6 -alkyl (C=NR 9 )NRI 0 , Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R 9 , R'O and R" are each independently selected from hydrogen, an optionally substituted C-C 6 -alkyl, C 1 -C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C3-C 7 -cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; B and B 2 are each independently selected from -C=C-, -C(=O)-, -S(=0) 2 -, -C=N or C which may further be substituted by Gq groups; WO 2005/123703 PCT/IB2005/002390 274 G4 groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-CI-C 6 -alkyl, O-Cr-C6-alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR1 2 , O-C-C 7 -cycloalkyl, O-Cr-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Co-C 6 -alkyl-OR 2 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, 0-C 3 -C 7 -cycloalkyl-Cl-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C6-alkyl-heteroaryl, aryl, 0-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR' 2 , Cr-C 6 -alkynyl-OR1 2 , C 3 C6-alkenyl-OR, Co-C 6 -alkyl-S-R 2 , 0 C 2 -C 6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R , O-C 2 -C 6 -alkyl-S(=O)-R, Co-C 6 -alkyl-S(=O) 2 -R 2 , O-Cr-C 6 -alkyl-S(=0) 2 -R 2 , Co-C 6 -alkyl NR R , O-C 2 -C 6 -alkyl-NR' 2 R 3 , Co-C 6 -alkyl-S(=O) 2 NR1 2 R 13 , Co-C 6 alkyl-NR 2 -S(=0) 2 R", O-C-C 6 -alkyl-S(=0) 2 NR 2 R 1 3 , O-C 2 -C 6 -alkyl NR-S(=0)2R , Co-C 6 -alkyl-C(=O)-NR1 R, Co-C 6 -alkyl NR12 C(=)-R1, O-C-C 6 -alkyl-C(=O)-NR' 2 R, 0-CrC6-alkyl NR 2 C(=O)-RI 3 , Co-C 6 -alkyl-OC(=O)-R 12 , Co-C 6 -alkyl-C(=O)-OR1 2 , O-C 2 -C 6 -alkyl-OC(=O)-R1 2 , O-C-C 6 -alkyl-C(=0)-OR , Co-C 6 -alkyl C(=O)-R' 2 , O-C-C 6 -alkyl-C=O)-R 2 , Co-C 6 -alkyl-NR12-C(=O)-OR 1 3 , Co-C 6 -alkyl-O-C(=O)-NR R or Co-C 6 -alkyl-NR' 2 -C(=O)-NR R14 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C6-alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Cr-C 6 -alkyl, O-C 3 -C 7 cycloalkyl-C-C 6 -alkyl, O-heteroaryl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from 1 to 5; R12, R" and R 1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, CI-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
14. A compound according to claim 2 having the formula II-B w Zia N 7 Gq II-B WO 2005/123703 PCT/IB2005/002390 275 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R2 R2 R2 RR 1 R2 1 R 1 R R 2 R 2 NR R3 N R RaNb R R< R 3 N R R 3 NA R 2 R' R 2 R 1 CI ->-0 ZII >rZ< R2 R2 R A'" R 1 , R 2 ,R 3 , R 4 , R' and A" are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C1-C 6 -alkyl, Ci-Cs-alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, 0-C 1 -C 6 -alkyl, 0-C 1 -C 6 -alkylhalo, 0-C 3 -C 6 -alkynyl, 0-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , 0-C 3 -C 7 -cycloalkyl, 0-C1-C6-alkcyl heteroaryl, O-C1-C6-alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkcyl-C 1 -C 6 -alkyl, O-C3-C 7 -cycloalkyl-C 1 -C 6 -alkyl, 0 heteroaryl, heteroaryl, C 1 -C 6 -alkyl-heteroaryl, aryl, 0-aryl, C 1 -C 6 alkylaryl, C 1 -C 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR 6 , C 3 -C 6 -alkenyl OR , Co-C 6 -alkyl-S-RR, -C 2 -C 6 -alkyl-S-R, Co-C 6 -alkyl-S(=0)-R _ 0 C 2 -C 6 -alkyl-S(=0)-R 6 , Co-C 6 -alkcyl-S(=0) 2 -R 6 , O-C1-C 6 -alkyl-S(=0) 2 R6, Co-C 6 -alkyl-NRR 7 , O-C 2 -C 6 -alkyl-NR 6 R 7 , Co-C 6 -alkyl S(=0) 2 NR 6 R 7 , Co-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , 0-C1-C 6 -alkyl S(=0) 2 NR 6 R 7 , 0-C1-C 6 -alkcyl-NR6-S(=O) 2 R 7 , Co-C 6 -alkyl-C(=0) NR 6 R 7 , Co-C 6 -alkyl-NR 6 C(=0)-R 7 , O-C1-C 6 -alkyl-C(=0)-NR 6 R 7 , 0 C 2 -C 6 -alkyl-KR 6 C(=0)-R 7 , Co-C 6 -alkyl-OC(=0)-R 6 , Co-C 6 -alkyl C(=0)-OR 6 , O-C 2 -C 6 -alkyl-OC(=0)-R 6 , O-C1-C 6 -alkyl-C(=O)-OR 6 , Co-C 6 -alkyl-C(=0)-R 6 , 0-C1-C 6 -alkyl-C(=0)-R 6 , Co-C 6 -alkyl-NR 6 _ C(=0)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR 6 R 7 or Co-C 6 -alkcyl-NR 6 -C(=0) NRR substituents; wherein optionally two sub stituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with WO 2005/123703 PCT/IB2005/002390 276 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C 1 -C 6 -alkylhalo, C 2 -C6-alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-Cr-C 6 -alkyl-heteroaryl, O-CI-C 6 alkylaryl, C-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, O-aryl; R 6 , R and R 8 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkyihalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C3-C7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 Am groups; m is an integer from 1 to 5; X is selected from an optionally substituted C-C 6 -alkyl, Cl-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 -cycloalkyl, Co-C 6 -alkyl-O, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Co-C6-alkyl, S-CO-C 6 -alkyl, C-C 6 alkylhalo-O, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=0), Co-C 6 -alkyl-S(=0)2, Co-C 6 -alkyl-NR 9 , Co-C 6 -N 9 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=O)-NR, Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=0), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=0)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR'o, Co-C 6 -alkyl-NR-C(=NR')NR", Co-C 6 -alkyl (C=NR 9 )NR" 0 , Co-C 6 -alkyl-C(=O)-O-CO-C6-alky1, Co-C 6 -alkyl-C(=O) NR 9 -Co-C 6 -alkyl, Co-C 6 -alky-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R', R'O and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalky-C-C6-alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; Z 9 , Z1 0 , Z 1 and z 1 2 are each independently selected from the group consisting of -C=, -C=C-, -C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 4 Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, 0-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR1 O-C 3 C 7 cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR' 2 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, WO 2005/123703 PCT/IB2005/002390 277 Cl-C6-alkyl-heteroaryl, aryl, 0-ary1, Cr-C 6 -alkylaryl, CI-C 6 -alkylhalo OR' 2 , C 3 -C 6 -alkynyl-OR' 2 , C 3 -C 6 -alkenyl-OR1 2 , Co-C 6 -alkyl-S-R", 0 C 2 -C 6 -alkyl-S-R1 2 , Co-C 6 -akyl-S(0)-R12, -C 2 -C 6 -alkyl-S(=O)-R12 Co-C 6 -alkyl-S(=O) 2 -R2', O-C-C 6 -alkyl-S(=0) 2 -R 2 , Co-C 6 -alkyl NR2R 13, 0-CrC6alkyl-NR1R1, Co-C 6 -alkyl-S(=O) 2 NR 2 R, Co-C6 alkyl-NR-S(=0)2R1, O-CrC6-alkyl-S(=0)2NR 2R , O-C 2 -C 6 -alkyl a NR 'S(=0)2R 1 3 Co-C 6 -alkyl-C(=)-NR R , Co-C 6 -alkyl NRl 2 C(=O)-R1 3 , O-C-C 6 -alkyl-C(=O)-NR 12R , O-C 2 -C 6 -alkyl NR'C(=0)-R", Co-C 6 -alkyl-OC(=O)-R', C 0 -C 6 -alkyl-C(=0)-OR', O-C 2 -C 6 -alkyl-OC(=O)-R' 2 , O-Cr-C 6 -alkyl-C(=0)-OR 12 , Co-C 6 -alkyl C(=O)-R1 2 , O-C-C 6 -alkyl-C(=O)-R' 2 , Co-C 6 -alkyl-NR'-C(=O)-OR1 3 , C 0 -C 6 -alkyl-O-C(=O)-NR 2 R" or Co-C 6 -alkyl-NR1 2 -C(=O)-NR 3 R14 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 -alkyl, Cr-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, 0-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C1-C 6 -alky1, O-C 3 -C 7 cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl, 0-aryl; q is an integer from 1 to 4; R , R and R1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C,-C 6 -alkyl, CI-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-Cl-C6-alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
15. A compound according to claim 14 having the formula II-B 1 B 1 Gq N II-B1 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein WO 2005/123703 PCT/IB2005/002390 278 W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R 2 R 2 R' R RR2 R R 1 xN R 3 -N S]23-< NNN N N N R' - RR -N R - N O>NISNON N-0~ R 2 R 2 R 2 R R R R 3 R RR R N N J-'~ : R 2 R 1 R 2 R 1 R1 N- Z Z 2 R~ N R 4I- * N Z A 'i' R 5 R 5 R4 A m R', R2, R3, R, Ri and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, Cr-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C 7 -cycloalkyl, O-Cl-C 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-CI-C 6 -alkyl, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, O-aryl, CI-C 6 alkylaryl, C-C 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR6, C 3 -C 6 -alkenyl OR6, Co-C 6 -alkyl-S-R 6, O-C 2 -C 6 -alkyl-S-R , Co-C 6 -alkyl-S(=O)-R 6, 0 C 2 -C 6 -alkyl-S(=O)-R 6 , Co-C 6 -alkyl-S(=O) 2 -R 6 , O-CI-C 6 -alkyl-S(=0) 2 R6, Co-C 6 -alkylNR6R7, O-C 2 -C 6 -akyI-NR 6 R 7 , Co-C 6 -alkyl S(=0) 2 NR 6 R7, Co-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , O-C-C 6 -alkyl S(=O) 2 NR 6 R 7 , O-C 1 -C 6 -alkyl-NR 6 -S(=0) 2 R 7 , Co-C 6 -alkyl-C(=O) NR 6 R 7 , Co-C 6 -alkyl-NR 6 C(=O)-R 7 , O-C-C 6 -alkyl-C(=O)-NR 6 R 7 , 0 C 2 -C 6 -alkyl-NR 6 C(=O)-R 7 , Co-C 6 -alkyl-OC(=O)-R, Co-C 6 -alkyl 66 C(=O)-OR6, 0-C 2 -C 6 -alkyl-OC(=0)-R, O-C-C 6 -alkyl-C(=O)-OR 6 , Co-C 6 -alkyl-C(=O)-R 6 , O-CI-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR6_ C(=O)-OR 7 , Co-C 6 -alkcyl-O-C(=O)-NR 6 R7 or Co-C 6 -alkyl-NR 6 -C(=O) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-Cl-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-Cl-C 6 -alkyl-heteroaryl, O-C 1 -C 6 - WO 2005/123703 PCT/IB2005/002390 279 alkylaryl, CI-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-C3-C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, 0-aryl; R 6 , R 7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C3-C7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C,-C 6 -alkyl-heteroaryl, aryl; ZI, Z 2 Z 3 , Z 4 , Z, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by I to 5 A m groups; n is an integer from 1 to 5; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C-C 7 -cycloalkyl, Co-C 6 -alkyl-O, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Co-C 6 -alkyl, S-Co-C 6 -alkyl, Cr-C 6 alkylhalo-O, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6 -NR 9 S(=0) 2 , Co-C 6 -alkyl-S(=O) 2 NR 9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR' 0 , Co-C 6 -alkyl-NR 9 -C(=NR')NR", CO-C 6 -alkyl (C=NR 9 )NR", Co-C 6 -alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 9 -Co-C 6 -alkyl, Co-CG-alkyl-C(=NOR 9 ) or CC-C 6 -alkyl-O-N=CR 9 substituents; R', R") and R" are each independently selected from hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C2 C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; BI represents independently C or N which may further be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR1, 0-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-Cr-C6 alkylaryl, Co-C6-alkyl-OR1 2 , C 3 -C 7 -ycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, O-aryl, C-C 6 -alkylaryl, Ci-C 6 -alkylhalo OR , C 3 -C 6 -alkynyl-OR , C 3 -C 6 -alkenyl-OR , Co-C 6 -alkyl-S-R 2 , 0 C 2 -C 6 -alkyl-S-R' 2 , Co-C6-akyl-S(=0)-R1 2 , O-C 2 -C 6 -alkyl-S(=O)-R1 2 , Co-C 6 -alkyl-S(=0) 2 -R 2 , O-C-C 6 -alkyl-S(=0) 2 -R, Co-C 6 -alkyl NR12R13 -C 2 -C 6 -alkyl-NR' 2 R, Co-C6-alkyl-S(=0)2NR1R1, Co-C 6 alkyl-NR1 2 -S(=O) 2 R", O-C-C 6 -alkyl-S(=0) 2 NR1 2 R3', O-C 2 -C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 280 NR 12 -S(=0) 2 R, 13 Co-C 6 -alkyl-C(=O)-NR R , Co-C 6 -alkyl NR1 2 C(=O)-R", O-C 1 -C 6 -alkyl-C(=O)-NR R , O-C 2 -C 6 -alkyl NR12C(=O)-R", Co-C 6 -alkyl-OC(=O)-R , Co-C 6 -alkyl-C(=O)-OR 2 , O-C 2 -C 6 -alkyl-OC(=O)-R 12 , O-C,-C 6 -alkyl-C(=O)-OR 12 , Co-C 6 -alkyl C(=O)-R 2 , O-Cr(C6-alkyl-C=O)-R1, Co-C6-akyl-NR oC()-OR", Co-C 6 -alkyl-O-C(=0)-NR 2 R or Co-C6-alkyl-NR12-C(=0)-NR'R1 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted Cr C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C 1 -C 6 alkyl, O-CI-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 cycloalkyl, O-Cl-C 6 -alkyl-heteroary, O-C-C 6 -alkylaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-C 3 -C 7 -cycloalkyl-C-C 6 alkyl, 0-heteroaryl, heteroaryl, Cr-C 6 -alkyl-heteroaryl, aryl, 0-aryl; q is an integer from 1 to 2; R 12 , R1 3 and R are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, CI-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
16. A compound according to claim 14 having the formula II-B2 N, BI __', Gq II-B2 Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: WO 2005/123703 PCT/IB2005/002390 281 R2 R2 R2 OR3-N IR2N- sR R xR RR - 1 - R2- R, xR N s 1 R2 R I R R2 R NSS<N S N- N /> 11 /)+ R 2 _ h Rl-{ jJ R N R N N N N R N R 2 R 1 R 2 R 1 R 3 RI R 3 R1 R' R2 2 N R R N R NN RA"~N R3 3 R R 5 RR4 R, R 2 , R 3 , R 4 , R 5 and A m are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C7-cycloalkyl, O-C 1 -C 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-CI-C 6 -alkyl, O-C 3 -C7-cycloalkyl-C-C6-alkyl, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C-C 6 alkylaryl, Cl-C 6 -alkylhalo-OR', C 3 -C 6 -alkynyl-OR 6 , C 3 -C 6 -alkenyl OR 6 , Co-C 6 -alkyl-S-R 6 , O-C 2 -C 6 -alkyl-S-R 6 , Co-C 6 -alkyl-S(=O)-R 6 , 0 C 2 -C 6 -alkyl-S(=O)-R6, Co-C 6 -alkyl-S(=0) 2 -R, O-Cl-C 6 -alkyl-S(=0)2 R6, Co-C 6 -alkyl-NRR, O-C 2 -C 6 -alkyl-NR6R7, Co-C 6 -alkyl S(=0) 2 NR 6 R 7 , Co-C6-alkyl-NR 6 -S(=O) 2 R 7 , O-C-C 6 -alkyl S(=0) 2 NR 6 R 7 , O-C-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , Co-C 6 -alkyl-C(=O) NR6R, Co-C 6 -alkyl-NR C(=O)-R 7 , O-C-C 6 -alkyl-C(=O)-NR 6R 7 , 0 C 2 -C 6 -alYl-NR 6 C(=O)-R 7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl 6 6 C(=)-OR', O-C 2 -C 6 -alkyl-OC(=0)-R 6 , O-C 1 -C 6 -alkyl-C(=O)-OR, Co-C6-alkyl-C(=0)-R6, O-CrC6-alkyl-C(=0)-R 6 , Co-C 6 -alkyl-NR 6 _ C(=0)-OR7, Co-C6-alkyl-O-C(=O)-NR 6 R 7 or Co-C 6 -alkyl-NR 6 -C(=O) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OHu, nitro, an optionally substituted C-C 6 -alkyl, Cl-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-C-C 6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-Cr-C 6 alkylaryl, C-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cj C 6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 - WO 2005/123703 PCT/IB2005/002390 282 alkylhalo, C 2 -C 6 -aIkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-Cr-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Z , Z2, Z3, Z4, Z , Z6, Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 Am groups; m is an integer from 1 to 5; X is selected from an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C,-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 -cycloalkyl, Co-C 6 -alkyl-0, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Co-C6-alkyl, S-Co-C 6 -alkyl, C 1 -C 6 alkylhalo-O, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-O, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR 9 , Co-C 6 -NR'S(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR, Co-C 6 -alkyl-C(=0)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR' 0 , Co-C 6 -alkyl-NR 9 -C(=NR' 0 )NR' 1 , Co-C 6 -alkyl (C=NR 9 )NR' 0 , Co-C 6 -alkyl-C(=0)-O-Co-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 9 -Co-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R 9 , R' 0 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalky-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, heterocycle; B1 represents independently C or N which may further be substituted by one Gq group; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 -alkyl, O-Cr-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR12, O-C 3 -C 7 -cycloalkyl, 0-C-C 6 -alkyl-heteroaryl, 0-C 1 -C 6 alkylaryl, Co-C 6 -alkyl-OR 12 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, O-aryl, C-C 6 -alkylary1, C-C 6 -alkylhalo OR' 2 , C 3 -C 6 -alkynyl-OR1 2 , C 3 -C 6 -alkenyl-OR' 2 , Co-C 6 -alkyl-S-R 2 , 0 C 2 -C 6 -alkyl-S-R' 2 , Co-C 6 -alkyl-S(=O)-R' 2 , O-C 2 -C 6 -alkyl-S(=O)-R 2 , Co-C 6 -alkyl-S(=0)-R 1 2 , O-C-C 6 -alkyl-S(=0) 2 -R 2 , Co-C 6 -alkyl NR12 R13, O-C 2 -C 6 -alkyl-NR' 2 R 3 , Co-C 6 -alkyl-S(=0) 2 NR' 2 R 3 , Co-C 6 alkyl-NR -S(=0) 2 R 3, O-Cr-C 6 -alkyl-S(=0) 2 NR.2R", O-C 2 -C 6 -alkyl NR2-S(=0)2R13, Co-C 6 -alkyl-C(=O)-NR1 2 RI 3 , Co-C 6 -alkyl NR 2 C(=O)-R 3 , O-Cl-C 6 -alkyl-C(=O)-NR 2 R1 3 , O-C 2 -C 6 -alkyl NR 2 C(=O)-R 3 , Co-C 6 -alkyl-OC(=O)-R 12 , Co-C 6 -alkyl-C(=O)-OR1 2 , O-C 2 -C 6 -alkyl-OC(=O)-R 2 , O-C-C 6 -alkyl-C(=O)-OR 12 , Co-C 6 -alkyl C(=O)-R , O-C-C 6 -alkyl-C(=O)-R1 2 , Co-C 6 -alkyl-NRR 2 -C(=O)-OR 3 , WO 2005/123703 PCT/IB2005/002390 283 CO-C6-alkyl-O-C(=O)-NR2R" or Co-C 6 -alkyl-NR 2 _C(=O)-NR"R14 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted Ci C 6 -alkyl, C1-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -Cs-alkenyl, 0-C 1 -C 6 alkyl, O-C 1 -C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 cycloalkyl, O-Ci-C 6 -alkyl-heteroaryl, O-C 1 -C 6 -alkylaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, 0-C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl; q is an integer from 1 to 3; R1 2 , R1 3 and R 1 4 are each independently selected from the group consisting of hydrogen, an optionally substituted C1-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C-alklynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C1-C 6 -alkyl, heteroaryl, C1-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
17. A compound according to claim 2 having the formula II-C W B==B2 X- B 3 Gq II-C Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: WO 2005/123703 PCT/IB2005/002390 284 R 2 R2 R2 s - ~ R NXR R 3 -N R 2< R x R< R 1 2R 2 INR x NRR R2R - R2 R N R 2 N R 3 N p 2 N N N J, RR R 3 R aR R N R 2 R 1 R 2 R 1 Ri R ' R R R N R R 3 ~N R- 3Z Z3Z2 R ' N R 3 " N Z. R t NTIN R, R 2 , R 3 , R 4 , R and Am are each independently selected from the group consisting of hydrogen, halogen, CN, OH, ntro, an optionally substituted Cr-C 6 -alkyl, Ci-C 6 -alkylhalo, C 2 -C 6 -alkyny1, C 2 -C 6 alkenyl, O-C 1 -C 6 -alky1, O-C1-C 6 -alkylhalo, O-C3-C 6 -alkynyl, 0-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -Cr-cycloalkyl, O-Cr-C 6 -alkyl heteroaryl, O-C 1 -C 6 -alkylary1, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 Cr-cycloalkyl-Cr-C 6 -alkyl, 0-C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, 0 heteroaryl, heteroaryl, Cr-C 6 -alkcyl-heteroary1, aryl, 0-aryl, Cr-C 6 alkylary1, C 1 -C 6 -alkylhalo-OR 6 , C 3 -C 6 -alkynyl-OR 6 , C 3 -C 6 -alkenyl OR , Co-C 6 -alkyl-S-R6, 0-C 2 -C 6 -alkyl-S-R6, Co-C 6 -akyl-S(=0)-RE, 0 C 2 -C 6 -alkyl-S(=0)-R 6 , Co-C 6 -alkyl-S(=0) 2 -R 6 , O-Cr-C 6 -alkyl-S(=0) 2 R 6 , Co-C 6 -alkyl-NR 6 R 7 , O-Cr-C 6 -alkyl-NR 6 R 7 , Co-C 6 -alkyl S(=0) 2 NR 6 R 7 , Co-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , 0-Cr-C 6 -alkyl S(=0) 2 NR 6 R 7 , 0-Cr-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , Co-C 6 -alkyl-C(=0) NRR, Co-C 6 -alkyl-46C(=0)-R, O-CrC 6 -alkyl-C(O)-NR 6 R 7 , 0 C 2 -C 6 -alkyl-NR 6 C(=0)-R 7 , Co-C 6 -alkyl-OC(=0)-R 6 , Co-C 6 -alkyl C(=O)-OR 6 , O-C 2 -C 6 -alkyl-OC(=0)-R 6 , O-Cr-C 6 -alkyl-C(=0)-OR 6 , Co-C 6 -alkyl-C(=0)-R6, o-CrC 6 -alkyl-C(=0)--R, Co-C 6 -alkyl-NR6_ C(=O , Co- C 6-alky l -kylO-C(=0)-NR 6 R 7 or Co-C 6 -alkyl-NR 6 -C(=0) NR 7 R 8 substituents; wherein optionally two sub stituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C C 6 -alkyl, C rC 6 -alkylhalo, C C 6 -alkynyl, CrC 6 alkenyl, 0-CrC 6 -alkyl, 0-Cr C 6 -alkylhalo, 0-CrC 6 -alkynyl, -C 3 rC 6 alkenyl, 0-CrC 7 -cycloalkyl, O-CrC 6 -alkyl-heteroaryl, O-C-C 6 alkylaryl, Cr-C 6 -alkylaryl, CCcycloalkyl, C-C-cycloalkyl-CrC 6 alkyl, 0-CC 7 -cycloalkyl-C-C 6 -aly1, 0-heteroaryl, heteroaryl, Cr C 6 -alkyl-heteroaryl, aryl, 0-ary1; R 6 , R 7 and Rw are each independently selected from the group consisting of hydrogen, an optionally substituted Cr-C 6 -alkyl, Cr-C 6 - WO 2005/123703 PCT/IB2005/002390 285 alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; ZI, Z2, Z3, Z 4 , ZI, Z 6 , Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from i to 5; X is selected from an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-Co-C 6 -alkyl, O-C-C 6 -alkylhalo, 0 C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, 0-C 3 -C 7 -cycloalkyl, Co-C 6 -alkyl-O, C3-C 7 -cycloalkyl, C3-C 7 -cycloalkyl-C 0 -C 6 -alkyl, S-Co-C 6 -alkyl, C-C 6 alkylhalo-0, C 3 -C 6 -alkynyl-O, C 3 -C 6 -alkenyl-0, Co-C 6 -alkyl-S, Co-C 6 alkyl-S(=O), Co-C 6 -alkyl-S(=0) 2 , Co-C 6 -alkyl-NR, Co-C 6 -NR 9 S(=0) 2 , Co-C 6 -alkyl-S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=0)-NR 9 , Co-C 6 -alkyl NR 9 C(=O), Co-C 6 -alkyl-OC(=O), Co-C 6 -alkyl-C(=O)-O, Co-C 6 -alkyl C(=O), Co-C 6 -alkyl-NR 9 -C(=O)-O, Co-C 6 -alkyl-O-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 -C(=O)-NR" 0 , Co-C 6 -alkyl-NR 9 -C(=NR1 0 )NR", Co-C 6 -alkyl (C=NR 9 )NR 0 , Co-C6-alkyl-C(=O)-O-CO-C 6 -alkyl, Co-C 6 -alkyl-C(=O) NR 9 -CO-C 6 -alkyl, Co-C 6 -alkyl-C(=NOR 9 ) or Co-C 6 -alkyl-O-N=CR 9 substituents; R9, R" and R" are each independently selected from the group consisting of hydrogen, an optionally substituted C-C-alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalky-C-C 6 -alkyl, heteroaryl, C,-C 6 -alkyl-heteroaryl, aryl, heterocycle; B', B 2 and B 3 are each independently selected from C or N which may further be substituted by Gq groups; G4 groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-CI-C 6 -alkyl, O-Cl-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C2-C 6 -alkyl OR 1 O-C 3 -C 7 -cycloalkyl, O-Cl-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR 12 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cy6loalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, Cl-C 6 -alkyl-heteroaryl, aryl, 0-aryl, Cl-C 6 -alkylaryl, C-C 6 -alkylhalo OR 12, C 3 -C 6 -alkynyl-OR , C 3 -C 6 -alkenyl-OR , Co-C 6 -alkyl-S-R , O C 2 -C 6 -alkyl-S-R 2 , Co-C 6 -alkyl-S(=O)-R 2 , O-C 2 -C 6 -alkyl-S(=O)-R' 2 , Co-C 6 -alkyl-S(=0) 2 -R2', O-C-C 6 -alkyl-S(=0) 2 -Rl 2 , Co-C 6 -alkyl NR' 2 R", O-C 2 -C 6 -alkyl-NR' 2 R", Co-C 6 -alkyl-S(=O) 2 NR R , Co-C 6 alkyl-NR1 2 -S(=0) 2 R, O-C-C 6 -alkyl-S(=O) 2 NR1 2 R 3 , O-C 2 -C 6 -alkyl NR-S(=0)2R, 13 Co-C 6 -alkyl-C(=O)-NR R3, Co-C 6 -alkyl NR 12 C(=O)-R 3 , O-C-C 6 -alkyl-C(=O)-NR R , 0-C 2 -C 6 -alkyl NR1 2 C(=O)-R 3 , Co-C 6 -alkyl-OC(=0)-R 2 , Co-C 6 -alkyl-C(=O)-OR1 2 , O-C 2 -C 6 -alkyl-OC(=O)-R 2 , O-C-C 6 -alkyl-C(=O)-OR 2 , Co-C6-alkyl C(=O)-R' 2 , O-C,-C 6 -alkyl-C(=O)-RI 2 , Co-C 6 -alkyl-NR1 2 -C(=O)-OR 3 , WO 2005/123703 PCT/IB2005/002390 286 Co-C 6 -alkyl-O-C(=0)-NR1 2 R" or Co-C 6 -alkyl-NR 1 2 -C(=O)-_NR"R 1 4 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent halogen, CN, OH, nitro, an optionally substituted C 1 C 6 -alkyl, C 1 -C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C 1 -C 6 alkyl, O-C1-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 3 -C 7 cycloalkyl, O-Ci-C 6 -alkyl-heteroaryl, O-C1-C 6 -alkylaryl, C 3 -C 7 cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C 1 -C 6 alkyl, 0-heteroaryl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl, 0-aryl; q is an integer from I to 5; R", R1 3 and R" are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-C 6 -alkyl, C 1 -C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C 1 -C 6 -alkyl, heteroaryl, CI-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; provided that: when X is independently selected from NRis, 0, S or an optionally substituted Ci-C 6 -alkyl, Gq and q are as defined above, W is an optionally substituted 2-pyridinyl and R 15 is independently selected from hydrogen, an optionally substituted C1-C 6 -alkyl, C1-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C1 C 6 -alkyl, heteroaryl, C1-C 6 -alkyl-heteroaryl or aryl, B1, B2 and B3 can not be C; when X is 0, B 1 , B 2 and B3 are each independently selected from C or N, Gq and q are as defined above, W can not be an optionally substituted 3-pyridazinyl or 4-pyrimidinyl; when X is CH 2 , B 1 , B 2 and B3 are C and Gq and q are as defined above, W can not be 2-phenyloxazol-4-yl, 4-phenyloxazol-2-yl, 4-(3 (benzyloxy)propyl)-oxazol-2-yl, 4-phenylthiazol-2-yl, 4-methylthiazol 2-yl, benzo[d]oxazol-2-yl or benzo[d]thiazol-2-yl; when X is 0, W is an optionally substituted pyridinyl and Gq and q are as defined above, B1, B2 or B 3 can not be N; when X is CH 2 CH 2 , B 1 , B 2 and B 3 are C and Gq and q are as defined above, W can not be 4-imidazolyl.
18. A compound according to claim 17 having the formula II-C WO 2005/123703 PCT/IB2005/002390 287 x G4 II-C Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from the group consisting of C, N, 0 and S; provided that W is a heteroaryl selected from the group of formula: R 2 R2 R2 R 1 1 % ORa-N R2~K jNjR R2< R - R - R2 R' N- 0 R 2 N N N N RR 1 R 3 R R 3 R3 N 1 R 2 N R N ,R R 2 R 1 R 2 R1 RR : N N N-0N R2 N R3 N 1 R 2 NV N NN RGR RR R', R 2 , R 3 , R 4 , RR and Am are each independently selected from the group consisting of hydrogen, halogen, CN, 0OH, nitro, an optionally substituted Cr-C 6 -alkcyl, Cr-C 6 -alkylhalo, C 2 -C 6 -alkyny1, C 2 -C 6 alkenyl, 0-Cr-C 6 -alkyl, 0-Cr-C 6 -alkylhalo, 0-Cr-C 6 -alkyny1, 0-CrC6 alkenyl, O.-C 2 -C 6 -alkyl-OR 6 , O-Cr-C 7 -cycloalkyl, 0-Cr-C 6 -alkyl heteroaryl, O-Cr-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , Cr-Crcycloalkyl, Cr C 7 -cycloalkyl-C3C 6 -alkyl, 0-CrCZcycloalkyl-CrC 6 -alkyl, 0 heteroaryl, heteroaryl, C 1 -C 6 -alkcy1-heteroary1, aryl, 0-aryl, Cr-C 6 alkylaryl, Cr-C 6 -alkylhalo-OR 6 , Cr-C 6 -alkynyl-OR6, Cr-C 6 -alkenyl OR , Co-C 6 -alkcyl-S-R , 0-C 2 -C 6 -alkyl-S-R6, Co-C 6 -alkyl-S(=0O)-R6, 0 C 2 -C 6 -alkyl-S(=0)-R 6 , Co-C 6 -alkyl-S(=0) 2 -R 6 , 0-Ci-C 6 -alkyl-S(=0) 2 R6, Co-C 6 -alkyl-NR6R7, O-C 2 -C 6 -alkyl-N7 6 R 7 , Co-C 6 -alkyl S(=0)2NR 6 R 7 , Co-C 6 -alkyl-NR 6 -S(=0) 2 R 7 , O-Cr-C 6 -alkyl S(=0) 2 NR 6 R", O-C 1 -C 6 -alkyl-NR 6 -S(=O) 2 R 7 , Co-C 6 -alkyl-C(=0) NR 6 R 7 , Co-C 6 -alkyl-NR 6 C(=0)-R 7 , 0-Cr-C 6 -alkyl-C(=0)-NR 6 R 7 , 0 C 2 -C 6 -alkyl-NR 6 C(=0)-R 7 , Co-C 6 -alkyl-OC(=)-R 6 , Co-C 6 -alkyl C(=0)-OR 6 , 0-C 2 -C 6 -alkcyl-OC(=0)-R 6 , 0-CrC 6 -alkcyl-C(=0)-OR 6 , Co-C 6 -alkcyl-C(=0)-R 6 , 0-Ci-C 6 -alkcyl-C(=0)-R 6 , Co-C 6 -alkyl-NR 6 _ WO 2005/123703 PCT/IB2005/002390 288 C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NRR or Co-C 6 -alkyl-NR 6 -C(=O) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-Cl-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-CI-C 6 alkylaryl, C-C 6 -alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, O-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, 0-aryl; R6, R7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; ZI, Z2, Z3, Z , Z , Z6, Z 7 and Z 8 are each independently selected from the group consisting of -C=, -C=C-, -0-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted C 2 -C 6 -alkynyl, Co-C 6 -alkyl NR'S(=O) 2 , Co-C 6 -alkyl-S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=O)-NR 9 , Co-C 6 alkyl-NR 9 C(=O), Co-C 6 -alkyl-C(=0)-O-C-C 6 -alkyl, Co-C 6 -alkyl C(=O)-NR 9 -Co-C 6 -alkyl, Co-C 6 -alkyl-OC(=O) or Co-C 6 -alkyl-C(=O)-O substituents; R9 is selected from hydrogen, an optionally substituted C-C 6 -alkyl, C C 6 -alkylhalo, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalky-C-C 6 -alkyl, heteroaryl, Ci-C 6 -alkyl-heteroaryl, aryl; B 1 , B 2 and B 3 are each independently selected from C or N which may further be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C6-alkenyl, O-C-C 6 -alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 -alkenyl, O-C 2 -C 6 -alkyl OR1 0 , O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, O-CI-C 6 alkylaryl, Co-C 6 -alkyl-OR" 0 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, O-heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, O-aryl, C-C 6 -alkylaryl, C-C 6 -alkylhalo OR", C 3 -C 6 -alkynyl-OR' , C 3 -C 6 -alkenyl-OR1 0 , Co-C 6 -alkyl-S-R 0 , 0 C 2 -C 6 -alkyl-S-R 10 , Co-C 6 -alkyl-S(=O)-R" 0 , 0-C 2 -C 6 -alkyl-S(=O)-Ri 0 , Co-C 6 -alkyl-S(=0) 2 -R" 0 , O-C1-C 6 -alkyl-S(=O) 2 -R1 0 , Co-C 6 -alkyl NRioR", O-C 2 -C 6 -alkyl-NR 0 R", Co-C 6 -alkyl-S(=O) 2 NR 0 R", Co-C 6 alkyl-NR1 0 -S(=O) 2 R1, O-C-C 6 -alkyl-S(=O) 2 NR' 0 Rr1, O-C 2 -C 6 -alkyl- WO 2005/123703 PCT/IB2005/002390 289 NR' 0 -S(=0) 2 R", Co-C 6 -alkyl-C(=0)-NR' 0 R1', Co-C 6 -alkyl NR' 0 C(=O)-R", O-C 1 -C 6 -alkyl-C(=0)-NR 0 RI', O-C 2 -C 6 -alkyl NR" 0 C(=O)-R", Co-C 6 -alkyl-OC(=O)-R 10 , Co-C 6 -alkyl-C(=O)-OR1 0 , O-C 2 -C 6 -alkyl-OC(=O)-R 0 , O-C 1 -C 6 -alkyl-C(=O)-OR 0 , Co-C 6 -alkyl C(=O)-R 0 , 0-C-C 6 -alkyl-C(=O)-R1 0 , Co-C 6 -alkyl-NR 10 -C(=O)-OR', Co-C 6 -alkyl-O-C(=O)-NR R or Co-C 6 -alkyl-NR 10 -C(=0)-NR R1 substituents; q is an integer from 1 to 5; R 0 , R" and R1 2 are each independently selected from the group consisting of hydrogen, an optionally substituted CrC 6 -alkyl, C-C 6 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C7-cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide.
19. A compound according to claim 17 having the formula II-C B B2 Gq II-C Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a 5-, 6- heterocyclic ring containing a N adjacent to the ethynyl bond, which ring may optionally be fused with a 5- or 6- membered ring containing one or more atoms independently selected from a group consisting of C, N, 0 and S; provided that W can not be a pyridine and W is a heteroaryl selected from the group of formula: WO 2005/123703 PCT/IB2005/002390 290 R 2 R 2 R 2 O1 R3-N R2 R x- , R NN2 R R R2 RR R 1N /> R_ N -: -0N >+o _: R21~ R 2 N R 3 N R2 N N s( N ss R 2 R 2 R1 N- R3 R 1 R N R R 2 N R' R 0J N N 3 N R 3N3 R 2 R 1 R 2 R 1 R 1 R 3 ~N\ R 2 ~ 6Z2 Z7Z2 R) ~ N-.N R 3 CN 'N V-2z -ZN' R 5 R R4An R1, R2, R3, R4, R5 and A! m are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-CI-C 6 -alkyl, O-Cl-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 2 -C 6 -alkyl-OR 6 , O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl heteroaryl, O-C-C 6 -alkylaryl, Co-C 6 -alkyl-OR 6 , C 3 -C 7 -cycloalkyl, C 3 C 7 -cycloalkyl-C-C 6 -alkyl, O-C 3 -C 7 -cycloalkyl-CI-C 6 -alkyl, 0 heteroaryl, heteroaryl, C-C 6 -alkyl-heteroaryl, aryl, 0-aryl, C 1 -C 6 alkylaryl, C-C 6 -alkylhalo-OR6, C 3 -C 6 -alkynyl-OR6, C 3 -C 6 -alkenyl OR , Co-C 6 -alkyl-S-R 6 , O-C 2 -C 6 -alkyl-S-R6, Co-C 6 -alkyl-S(=O)-R 6, 0_ C 2 -C 6 -alkyl-S(=O)-R6, Co-C 6 -alkyl-S(=0) 2 -R6, O-C 1 -C 6 -alkyl-S(=O) 2 R 6 , Co-C 6 -alkyl-NR 6 R 7 , O-C 2 -C 6 -alkyl-NRR7, Co-C 6 -alkyl S(=0) 2 NR 6 R 7 , Co-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , O-CI-C 6 -alkyl S(=0) 2 NRR 7 , O-C,-C 6 -alkyl-NR 6 -S(=O) 2 R 7 , Co-C 6 -alkyl-C(=O) NR 6 R 7 , Co-C 6 -alkyl-NR 6 C(=O)-R 7 , O-Cr-C 6 -alkyl-C(=O)-NR 6 R 7 , 0 C 2 -C 6 -alkyl-NR 6 C(=O)-R 7 , Co-C 6 -alkyl-OC(=O)-R 6 , Co-C 6 -alkyl 66 6 C(=O)-OR6, O-C 2 -C 6 -alkyl-OC(=O)-R6, O-C-C 6 -alkyl-C(=O)-OR, CO-C6-alkyl-C(=O)-R6, O-C-C 6 -alkyl-C(=O)-R 6 , Co-C 6 -alkyl-NR 6 C(=O)-OR 7 , Co-C 6 -alkyl-O-C(=O)-NR R7 or Co-C 6 -alkyl-NR 6 -C(=O) NR 7 R 8 substituents; wherein optionally two substituents are combined to the intervening atoms to form .a bicyclic aryl, cycloalkyl, heterocycloalkyl or heteroaryl ring; wherein each ring is optionally further substituted with 1-5 independent hydrogen, halogen, CN, OH, nitro, an optionally substituted C-C 6 -alkyl, Cr-C 6 -alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 alkenyl, O-Cl-C6-alkyl, O-C-C 6 -alkylhalo, O-C 3 -C 6 -alkynyl, O-C 3 -C 6 alkenyl, O-C 3 -C 7 -cycloalkyl, O-C-C 6 -alkyl-heteroaryl, 0-C-C 6 alkylaryl, Cl-C6-alkylaryl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 alkyl, O-C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C C 6 -alkyl-heteroaryl, aryl, O-aryl; R6, R7 and R8 are each independently selected from the group consisting of hydrogen, an optionally substituted Cl-C 6 -alkyl, C 1 -C 6 - WO 2005/123703 PCT/IB2005/002390 291 alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C7-cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, C1-C6-alkyl-heteroaryl, aryl; ZI, Z 2 , Z 3 , Z 4 , Zs, Z 6 , Z 7 and Z' are each independently selected from the group consisting of -C=, -C=C-, -o-, -N=, -N- or -S- which may further be substituted by 1 to 5 A m groups; m is an integer from 1 to 5; X is selected from an optionally substituted Ci-C-alkyl, C 2 -C 6 -alkynyl, O-Co-C 6 -alkyl, Co-C 6 -alkyl-O, O-C 3 -C 6 -alkynyl, S-Co-C 6 -alkyl, Co-C 6 alkyl-S, Co-C 6 -alkyl-S(=O), Co-C 6 -alkyl-S(=O) 2 , S(=O) 2 -Co-C 6 -alkyl-, Co-C 6 -alkyl-NR', NR 9 -Co-C 6 -alkyl, Co-C 6 -NR 9 S(=0) 2 , Co-C 6 -alkyl S(=0) 2 NR 9 , Co-C 6 -alkyl-C(=0O)-NR, Co-C6-alkyl-NR 9 C(=O), Co-C 6 alkyl-C(=O)-O-Co-C 6 -alkyl, Co-C6-alkyl-C(=0)-NR9-Co-C6-alkyl, C(=O)-Co-C 6 -alkyl or Co-C 6 -alkyl-C(=O) substituents; R 9 is selected from hydrogen, an optionally substituted C,-C 6 -alkyl, Ci C 6 -alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 -alkenyl, C3-C 7 -cycloalkyl, C 3 -C 7 cycloalky-C-C 6 -alkyl, heteroaryl, C,-C6-alkyl-heteroaryl, aryl; B', B 2 and B 3 are each independently selected from C or N which may further be substituted by Gq groups; Gq groups are each independently selected from the group consisting of hydrogen, halogen, CN, OH, nitro, an optionally substituted CI-C 6 alkyl, Cr-C 6 -alkylhalo, C2-C 6 -alkynyl, C 2 -C 6 -alkenyl, O-C-C 6 -alkyl, O-C,-C 6 -alkylhalo, 0-C 3 -C 6 -alkynyl, O-C3-C 6 -alkenyl, O-C 2 -C 6 -alkyl OR1, O-C 3 -C 7 -cycloalkyl, O-C-C6-alkyl-heteroaryl, 0-C-C 6 alkylaryl, Co-C 6 -alkyl-OR'o, C3-C 7 -cycloalkyl, C3-C 7 -cycloalkyl-C, C6-alkyl, O-C3-C7-cycloalkyl-C-C 6 -alkyl, 0-heteroaryl, heteroaryl, C-C6-alkyl-heteroaryl, aryl, 0-aryl, C1-C6-alkylaryl, C-C 6 -alkylhalo OR'O, C 3 -C 6 -alkynyl-OR' 0 , C 3 -C 6 -alkenyl-OR 0 , Co-C 6 -alkyl-S-R" 0 , 0 C 2 -C 6 -alkyl-S-R 1 0 , Co-C 6 -alkyl-S(=O)-R1 0 , O-C 2 -C 6 -alkyl-S(=O)-R' 0 , Co-C 6 -alkyl-S(=0) 2 -R', O-CI-C 6 -alkyl-S(=0) 2 -R1 0 , Co-C 6 -alkyl NR' 0 R", O-C2-C 6 -alkyl-NR 0 R", Co-C 6 -alkyl-S(=O) 2 NR 0 R', Co-C6 alkyl-NR' 0 -S(=0) 2 R", O-CI-C 6 -alkyl-S(=O),NR'R'1, O-C 2 -C 6 -alkyl NRIC-S(=0)2R Co-C 6 -alkyl-C(=)-NR' 0 R' 1 , Co-C6-alkyl NR 0 C(=O)-R ', O-C-C 6 -alkyl-C(=O)-NR' 0 R", O-C2-C 6 -alky1 NR 10 C(=O)-R", Co-C6-alkyl-OC(=O)-R 0 , Co-C 6 -alkyl-C(=O)-OR'O, 0-C 2 -C 6 -alkCyl-OC(=O)-R", O-C-C 6 -alkyl-C(=0)-OR 0, Co-C 6 -alkyl C(=O)-R' 0 , O-CI-C6-alkyl-C(=O)-R 10 , Co-C 6 -alkyl-NR1'-C(=O)-OR", Co-C6-alkyl-O-C(=O)-NR"1R or Co-C6-alkyl-NR1 0 -C(=O)-NR R1 substituents; q is an integer from 1 to 5; R' 0 , R" and R1 2 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C 1 -C 6 - WO 2005/123703 PCT/IB2005/002390 292 alkylhalo, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 cycloalkyl-C-C 6 -alkyl, heteroaryl, CI-C 6 -alkyl-heteroaryl, aryl; Any N may be an N-oxide; provided that: when X is 0, B 1 , B 2 and B 3 are each independently selected from C or N, G' and q are as defined above, W can not be an optionally substituted 3-pyridazinyl or 4-pyrimidinyl; when X is CH 2 , B 1 , B 2 and B 3 are C and Gq and q are as defined above, W can not be 2-phenyloxazol-4-yl, 4-phenyloxazol-2-yl, 4-(3 (benzyloxy)propyl)-oxazol-2-yl, 4-phenylthiazol-2-yl, 4-methylthiazol 2-yl, benzo[d]oxazol-2-yl or benzo[d]thiazol-2-yl; when X is CH 2 CH 2 , B 1 , B 2 and B 3 are C and Gq and q are as defined above, W can not be 4-imidazolyl.
20. A compound according to claim 2 having the formula II II Or a pharmaceutically acceptable salt, hydrate or solvate of such compound Wherein W is a heteroaryl selected from the group of formula: R 2 R2 R2 R3-N R R RR R RN NRN R N R 4 NA R 1 , R 2 , R 3 and R4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted CI-C 6 -alkyl, CI-C 6 -alkylhalo, aryl, Co-C 6 -alkyl-ORs, Co-C 6 -alkyl-NR 5 R 6 , Co-C 6 alkyl-NRC(=O)-Ror Co-C 6 -alkyl-NR 5 S(=0) 2 -Rsubstituents; Rs and R6 are each independently selected from the group consisting of hydrogen, an optionally substituted CI-C 6 -alkyl, C-C 6 -alkylhalo, C 3 C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-C 6 -alkyl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl; X is selected from an optionally substituted C-C 6 -alkyl or CrC6 alky1halo; WO 2005/123703 PCT/IB2005/002390 293 W' is selected from: N Gq groups are each independently selected from the group consisting of hydrogen, halogen, nitro, an optionally substituted C-C 6 -alkyl, C-C 6 alkylhalo, Co-C 6 -alkyl-OR 7 , O-Co-C 6 -alkylaryl, heteroaryl, aryl, Co-C 6 alkyl-NRR 8 or Co-C 6 -alkyl-NR 7 -S(=0) 2 R 8 substituents; q is an integer from 1 to 5; R and R 8 are each independently selected from hydrogen, an optionally substituted C-C 6 -alkyl, C-C 6 -alkylhalo; Any N may be an N-oxide.
21. A compound according to claims 1 to 20, wherein said compound is selected from: 2-Methyl-(4-(4-phenyl)but-1-ynyl)tbiazole 2-(4-(3-(2-Ethylphenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(Pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione 2-(4-(Pyridin-2-yl)but-3-ynyl)phthalazin-1(2H)-one 2-(4-Phenylbut-1-ynyl)quinoline 2-(4-Phenylbut-1-ynyl)pyrimidine 2-(4-Phenylbut-1-ynyl)benzo[d]oxazole 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 2 -( 4 -(Pyridin-2-yl)but-3-ynyl)benzo[d]oxazole hydrochoride 2-(4-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-Pheny)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-Methyl-4-(4-phenylbut-1-ynyl)-lH-imidazole N-Methyl-N-phenyl-5-(pyridin-2-y)pent-4-ynamide N-( 4 -Fluoropheny)-N-methyl-5-(pyridin-2-yl)pent-4-ynaniide 2-(4-(2-Phenylthiazol-4-yl)but-1-ynyl)pyridine 2-(4-(3-o-Tolyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-benzyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(2-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(2-Methylbenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(4-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(4-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-Isopropyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-Butyl-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(3-Fluorobenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(3-Methoxybenzyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(2-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3-(3-Fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 5-Chloro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 5-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole WO 2005/123703 PCT/1B20051002390 294 6-Methyl-(2-(4-pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 4-Methyl-(2-(4-pyridin-2-yl)but-3 -ynyl)benzo[d] oxazole 2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)benzo [d]oxazole 2-(4-(5-Phenyl-2H--tetrazol-2-yl)but-1-ynyl)pyridine N-{4-Fluorophenyl)-5-(pyridine-2-yl)pent-4-ynamide 2-(4-(Pyridin-2-y)but-3-yny)benzo[dIthiazole 6-Chloro-(2-(4-pyridini-2-yl)but-3-ynyl)benzo[d]oxazole 5-Fluoro-(2-(4-pyridin-2-yl)but-3-ynyl)benzo~d]oxazole 2-(6-(4-IFluoropheniyl)hexa- 1,5-cliynyl)pyricline 2-(4-(3-(2-Methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)but- 1 -ynyl)pyridine 2-(4-(3-(3-Methoxyphenyl)-1 ,2,4-oxadiazol-5-yl)bub 1 -ynyl)pyricline 2-(4-(3 -{4-Methioxyphenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -in-Tolyl- 1,2,4-oxadiazol-5-yl)but- 1 -ynyl)pyridi-ne 2-(4-(3-p-Tolyl- 1,2,4-oxadiazol-5-yl)buat- 1-ynyl)pyridine 2-(4-(3-(2-Chlorophenyl)- 1,2,4-oxadiazol-5-yl)buat-1-ynyl)pyridine 2-(4-(3 -(3 -Chlorophenyl)- 1,2,4-oxadiazol-5-yl)but-1-yriyl)pyridine 2-(4-(3 -(4-Chilorophenyl)- 1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine 2-(4-(3 -(2,6-Dimethylphenyl)- 1,2,4-oxadiazol-5-yl)but- 1 -ynyl)pyri dine 2-(4-(3-(2-Trifluoromethyl)phenyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3.-(Naphthalen- l-yl)-l ,2,4-oxadiazol-5-yl)but-l1-ynyl)pyridine 2-(4-(3 -(Naphthalen-2-yl)- 1,2,4-oxadiazol-5-yl)but-l1-ynyl)pyridine 2-(4-(3-(2,3-Dimethylphenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-(2,5-Dichlorophenyl)- 1,2,4-oxadiazol-5-yl)b-ut- 1 -ynyl)pyridine 2-(4-(3 -(2,5-dimethaylpheny1)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(2,6-Dichlorophenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-(2,3-Dichlorophenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-(2,4-Diclilorophenyl)- 1,2,4-oxadiazol-5-yl)b-ut- 1-ynyl)pyridine 2-(4-(3 -(2-Chloro-6-methylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-{4-(3 -(5-Fluoro-2-methylphenyl)-1 ,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3 -(5-Cbloro-2-methylphenyl)- 1,2,4-oxadiazol-5-yl)but- 1-ynyl)pyridine 2-(4-(3-(2-(Trifiuoromethoxy)phenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 7-Chloro-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo[dloxazole 7-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[djoxazole 2-(4-(5-Phenyloxazol-2-yl)but-1-ynyl)pyridine 2-(4-(3 -(3-Chloro-2-methylphenyl)- 1,2,4-oxadiazol-5-yl)but-1 -ynyl)pyridine 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo[dloxazol-4-ol 2-(4-(5-Fl-uoropyridin-2-yl)but-3-ynyl)benzo[d oxazole 4-Methoxy-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 2-(4-(Pyridin-2-y1)but-3-yny1)oxazolo[5,4-bI~pyridine 7-Chloro-5-fluoro-2-(4-(pyridin-2-yl)but-3 -y1)benzo[d]oxazole 2-(4-(Pyidin-2-y)but-3-yayl)oxazolo[4,5-bjpyridine 2-(4-(IPyridin-2-yl)but-3-ynyl)benzo [d]oxazole-5-carbonitrile 7-Chloro-5-fluoro-2-(4-(2-methyltbiazol-4-yl)but-3-ynyl)benzo[d]oxazole 7-(Tiifluoromethy)-2-(4-(pyridin-2-y)but-3-ny1)benzo [d]oxazole and pharmaceutically acceptable salts thereof
22. A compound according to claims 1 to 20 wherein said compound is selected from: WO 2005/123703 PCT/1B20051002390 295 7-Bromo-5-fluoro-2-(4-(pyidin-2-yl)but-3-ynyl)benzo~d]oxazole 5-Fluoro-7-phenyl-2-(4-(pyridin-2-y1)but-3-yny1)benzo[d] oxazole 2-(4-(2-Chloropyrimidin-4-yl)but-3 -ynyl)benzo Ed] oxazole 2-Chloro-4-(4-phenylbut- 1-ynyl)pyrimi.dine 4-Bromo-2-(4-(pyridin-2-yl)buat-3 -ynyl)benzo Ed] oxazole 4-Phenyl-2-(4-(pyridin-2-yl)buit-3 -ynyl)benzo [d] oxazole 4-Chloro-2-(4-(pyridin-2-yl)but-3 -ynyl)benzo Ed] oxazole 5,7-Difluoro-2-(4-(pyridin-2-y1)but-3-y1y)benzo[d] oxazole 4-Fluoro-2-(4-(pyridin-2-y1)but-3-yny1)benzo [d]oxazole 7-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d oxazole 2-(4-(Pyridin-2-yl)but-3-ynyl)benzo Ed] oxazole-7-carbonitrile 7-Chloro-4-.fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 7-Methoxy-2-(4-(pyridin-2-yl)but-3-y1y)benzo[d]oxazole 7-Jsopropyl-2-(4-(pyridin-2-yl)but-3-yniyl)beinzo[d]oxazole 4,7-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzoloxazole 7-Fluoro-4-(trifluoromethyl)-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole 2-(4-(Pyrirnidin-4-yl)but-3-ynyl)benzo[d]oxazole N-(3-Chloropheny)-N-methyl-5-(pyridin-2-y1)pent-4-ynanmide 7-Chloro-4-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 4-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 4,7-Dimnethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 4-Methyl-2.-(4-(pyridin-2-yl)but-3-ynyl)benzo [d] tbiazole 5-Fluoro-2-(4--(pyridin-2-yl)but-3-ynyl)benzo [d]tlfiazole 4-Cbloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole N-(2-CliAoropheny1)-N-methy1-5-(pyridin-2-y1)pent-4-ynarnide 1 -Methy1-2-(4-(pyridin-2-y1)but-3-yny1)- 1H-benzo[d]imidazole 2-(4-(Pyridin-2-yl)but-3-ynyl)-211-indazole 1 -(4-(pyridin-2-yl)but-3 -ynyl)-1H-indazole 2-(4-(5-Phenyl-1H-pyrazo-1-yl)but-1 -ynyl)pyridine 2-(4-(3-Phenylisoxazol-5-yl)but- 1-ynyl)pyricline 2-(4-(2-Methylthiazo1-4-y1)but-3-ynyl)benzo[dlthiazole 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]tbiazole 2-(4-(6-Methylpyridin-2-yl)b-ut-3-ynyl)benzo [d]thiazole 2-(4-(6-Chloropynidin-2-y)but--yny1)benzo[d]thiazole 7-Chiloro-4-fluoro-2.-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 2-(4-(6-Fluoropyridin-2-yl)but-3-ynyl)benzo[d]thiazole 2-(4-(Pyridin-2-yl)but-3-ynyl)quinoline 2-(4-(4-Phenyl-1H-pyrazol-1-yl)but- 1-ynyl)pyridine 7-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole 2-(6-(Pyridin-2-yl)hex-5-ynyl)-211-indazole 1 -(6-(pyridin-2-yl)hex-5-ynyl)- 1H-indazole 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoline 2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)quinoline 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline 2-(4--(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-21{-indazole 2-(4-(4-(4-Fluoropheny)-1H-pyrazo1-1 -yl)but- 1-ynyl)pyridine 2-(4-(4-o-Tolyl- 1H-pyrazol-1 -yl)but-1 -ynyl)pyridine 2-(Fluoromethyl)-6-(4-(4-o-tolyl- lH-pyrazol-l -yl)but- 1-ynyl)pyridine 2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)- 1H-pyrazol-1 -yl)but- 1-ynyl)pyridine WO 2005/123703 PCT/1B20051002390 296 6-Fluoro-2-(4-(6-(fl-aoromethyl)pyridin-2-yl)but-3 -ynyl)quinoxaline 6,7-Diflnoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)qunoxaline 4-Fluoro-2-(4-(6-(fluioromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole 4-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole 6-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole 4-Chloro-2-(4-(6-(fluaoromethyl)pyridin-2-yl)but-3-ynyl)-2{-indazole 7-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-21{-inldazole 2-(4-(3-Phenyl-1H-pyrazol- 1-yl)but-1 -yniyl)pyridine 2-(4-(3-(4-Fluorophenyl)isoxazol-5-yl)but- 1-ynyl)pyridine 2-(4-(5-(4-Fluorophenyl)-1H-pyrazol-1-yl)but- 1-ynyl)pyridine 2-( 1-Fluoro-4-(pyridin-2-yl)but-3-ynyl)quinoxaline 2-(4-(3-Methyl-4-phenyl- 1H-pyrazol- 1-yl)but-1 -ynyl)pyridine 2-(4-(5-methyl-4-phenyl- 1H-pyrazol-1-yl)but- 1-ynyl)pyridine 2-(4-(4-(4-Fluorophenyl)-1H-1 ,2,3-triazol- 1-yl)but- 1-ynyl)pyridine 2-(4-(6-(Fluoromethy1)pyridin-2-y1)but-3-yny1)-3-methylquinoxali-ne 2-(4-(Pyridin-2-yl)but-3 -ynyl)isoquinolin- 1(211)-one 2,6-Dimethoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benlzamide 2,6-Difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)pent-4-ynamide 2-(4-(Pyridini-2-yl)but-3-ynyl)isoindolin-1 -onie N-(2-Fludrophenyl)-5-(pyridin-2-yl)pent-4-ynamide IN-(3-Fluoropheniyl)-5-(pyridin-2-yl)pent-4-ynainide N-(4-Fluoro-2-methyl-phenyl)-5-(pyridin-2-yl)pent-4-ynamide 2,6-Dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide 2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzamide 2-Chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzenesulfonamide 2-Chloro-N-(4-(pyridin-2-yl)but-3 -ynyl)benzenesulfonamide 5-(6-(Fluoromethyl)pyridin-2-yl)-N-(4-fluoro-2-methyl-phenyl)pent-4-ynamide 5-(4-Fluoro-phenyl)- 1-(4-pyridin-2-yl-but-3-ynyl)- 1H-pyridin-2-one 2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-l11-1 ,2,3-triazol-1 -yt)but- 1-ynyl)pyridine 2-(4-(4-(4-Fluorophenyl)-2H- 1,2,3-triazol-2-yl)but- 1-ynyl)pyridine 2-(Fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1 ,2,3-tiazol-2-yl)but- 1-ynyl)pyridine 2-(4-(4-(4-Fluorophenyl)-5-methyl-21- 1 ,2,3-triazol-2-yl)but- 1-ynyl)pyridine 2-(4-(4-(4-Flnorophenyl)-5-methyl-l11-1 ,2,3-triazol- 1-y1)but- 1-ynyl)pyridine 2-(4-(4-(2-Chlorophenyl)-2H- 1,2,3-triazol-2-yl)but- 1-ynyl)pyridine 1 -(4-(4-(2-Chlorophenyl)-1H- 1,2,3 -triazol-2-yl)but- 1-ynyl)pyridine 2-(4-(6-(Fluoromethy1)pyridin-2-y1)but-3 -ynyl)-l1-methyl- 1H-benzo[d]iniidazole 7-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-l1-methyl-l11 benzo[d]imidazole 7-chioro-l1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)- 1H-benzo[d]imidazole 4,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)- -methyl-lU benzo[dlimidazole 1 -isopropy1-2-(4-(pyridin-2-yl)buat-3-ynyl)-1H-benzo[d]imidazole 1 -phenethyl-2-(4-(pyridin-2-yl)but-3 -ynyl)-l11-b enzo Ed] iiidazole 1 -benzyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole 5-fluoro-l -methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole 1 -(4-(pyridin-2-yl)but-3-ynyl)pyridin-2(1H)-one 3-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 3-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3 -ynyl)benzamide N-methyl-2-phenyl-N-(4-(pyridin-2-yl)but-3-ynyl)acetainide WO 2005/123703 PCT/IB2005/002390 297 N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)-2-(trifluoromethyl)benzamide 4-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-yny)benzamide 3-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 4-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide 2-chloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzenesulfonamide 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzene sulfonamide 2,6-dichloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide N,2-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 2-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide N,4-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide N,3-dimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 2-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide 2,3 -difluoro-N-methyl-N-(4-(pyridin-2-y1)but-3-ynyl)benzamide 2,6-dichloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide N,3,5-trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide N-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine 1-methyl-3-(5-(pyridin-2-yl)pent-4-ynyl)-lH-benzo[d]imidazol-2(3H)-one (3-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole 2-(4-(2-methyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole 2-(4-(1,2-dimethyl-1H-imidazol-4-yl)but-3-ynyl)benzo[d]oxazole 4-(pyridin-2-yl)but-3-ynyl 2-chlorobenzoate 4-(pyridin-2-yl)but-3-ynyl 3-chlorobenzoate 3-chlorophenyl 5-(pyridin-2-y1)pent-4-ynoate 3-chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate 2-chlorophenyl 5-(pyridin-2-yl)pent-4-ynoate 2-chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzo[d]thiazole 2-(5-(pyridin-2-yl)pent-4-ynyl)isoindoline-1,3-dione 2-(6-(pyridin-2-yl)hex-5-ynyl)phthalazin-1(2H)-one 1-methyl-3-(5-(pyridin-2-yl)pent-4-yny)-1H-benzo[d]imidazol-2(3H)-one N-(4-chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide N-(3-chlorophenyl)-5-(pyridin-2-yl)pent-4-ynamide N-(2,4-difluorophenyl)-5-(pyridin-2-yl)pent-4-ynamide and pharmaceutically acceptable salts thereof.
23. A compound according to claims 1 to 20 wherein said compound is selected from: 2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 8-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 5-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 2-(4-(2-Methylthiazol-4-yl)but-3-yny)imidazo[1,2-a]pyridine 6-Fluoro-2-(4-(pyridii-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine WO 2005/123703 PCT/1B20051002390 298 2-(4-(Pyridin-2-yl)but-3 -ynyl)-2H-benzo[d] [ 1,2,3]triazole l-(4-(pyridin-2-yl)but-3-ynyl)-lH-benzo[d] [l1,2,3]triazole 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo[i] [1 ,2,3]triazole hydrochloride 2-(5-(Pyridin-2-yl)pent--4-ynyl)-2H-benzo[d] [1 ,2,3]triazole l-(5(Pyridin-2-yl)pent-4-ynyl)-l1H-benzo[d] [1 ,2,3]triazole 1 -(6-(Pyridin-2-yl)hex-5-ynyl)-1H-benzo[d] [1 ,2,3]triazole 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-benzo[d] [1 ,2,3]triazole 5-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d] [1 ,2,3]triazole 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d] [ 1,2,3]triazole 2-(4-(6-(Fluloromethiyl)pyridin-2-yl)but-3-ynyl)-2}{-benzo[Jj [ 1,2,3]triazole hydrochloride 4,6-Difluoro-2-(4-(6-(fluaoromethyl)pyridin-2-yl)but-3-ynyl)-2H beuzo[c] [1 ,2,3]triazole 4,6-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H benzo[d][l ,2,3]triazole hydrochloride 4,5-Difluoro-2-(4-(6-(fl-aorometiyl)pyridin-2-yl)but-3-yiyl)-2H beizo [d] [1 ,2,3]triazole 4,5-Difluoro-2-(4.-(6-(fluoromethyl)pyridin-2-yl)b-ut-3-ynyl)-2H benzo [c] [1 ,2,3]triazole hydrochloride 2-(4-(6-(Difluoromethyl)pyridin-2-yl)but-3-ylyl)-2H-benzo [i] [1 ,2,3]triazole 4,6-Difluoro-2-(4-(pyridin-2-yl)but-3 -ynyl)-2H-benzo[d] [1 ,2,3]triazole 4,5-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d] [1 ,2,3]triazole 2-(4-(6-Methylpyridin-2-yl)but-3-ynyl)-211-benzo[d] [1 ,2,3]triazole 2-(4-(3 -Fluoropyridin-2-yl)but-3-ynyl)-2H-benzo [c] [1 ,2,3]triazole 5-Fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d] [1 ,2,3]triazole 2-(4-(2-Methyltliiazol-4-yl)but-3-ynyl)-2H-benzo [c] [1 ,2,3]triazole 4-Chloro-2-(4-(pyridin-2-yl)but-3 -yiiyl)-2H-benzo Ed][ l,2,3]triazole 4-Chloro-2-(4-(6-(fl-uoromethyl)pyridin-2-yl)but-3-ynyl)-21-benzo[d] [1 ,2,3]triazole 5,6-Difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-21-beizo[d] [1,2,3]triazole 5,6-Difluoro-2-(4-(6-(fl-aoromethyl)pyridin-2-yl)but-3-ynyl)-2H benzo[d][l,2,3]triazole 4-Chloro-2-(4-(l -methyl- 1H-pyrazol-3-yl)buat-3-ynyl)-2H-benzo[d] [1 ,2,3]triazole 6-(4-(4,6-Difluoro-2H-benzo[d] [1 ,2,3]triazol-2-yl)but-l -ynyl)pyridin-2-amine 2-(4-(2H-B enzo [c] [1 ,2,3]triazol-2-yl)but- 1-ynyl)-6-methylpyridin-3-ammie 4-Nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-beizo[d] [1 ,2,3]triazole 2-(4-(6-(Fluaoromethyl)pyridin-2-yl)but-3 -ynyl)-4-nitro-211-benzo [i] [1 ,2,3]triazole 2-(4-(Pyridin-2-yl)but-3-ynyl)-2H-benzo [i] [1 ,2,3]triazol-4-am~ine 4-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo [c] [1 ,2,3]trliazole 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-methyl-2H-benzo[d] [1 ,2,3]triazole 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-yayl)-5-methiyl-2H-benzo[d] [1 ,2,3]triazole 5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo [i] [1 ,2,3]triazole 6-(4-(2H-Benzo[d] [1 ,2,3]triazol-2-yl)but-l -ynyl)-N-methylpyridin-2-annine IN-(6-(4-(2H-Benzo[d][ 1,2,3]triazol-2-yl)but-l -ynyl)pyridin-2-yl)acetamide 6-(4-(2H-Benzo[d] [1 ,2,3]ftiazol-2-yl)but- 1-ynyl)-N-ethylpyridin-2-amine 'N-(6-(4-(2H-Benzo[i] [1 ,2,3]triazol-2-yl)but- 1-ynyl)pyridin-2-yl)methylsulfona'ide N-(6-(4-(2H-Benzo[d] [1 ,2,3lltriazol-2-yl)but- 1-ynyl)pyridin-2--yl)fonmamide 4-Chloro-2-(4-(l ,2-dimethyl- lH-imidazol-4-yl)but-3-ynyl)-21{ benzo[d][l ,2,3]triazole 4,5-Dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d] [l,2,3]triazole WO 2005/123703 PCT/IB2005/002390 299 2-(4-(6-(Fluoromethyl)pyridin-2-yl)but-3-ynyl)-4,5-dimethyl-2H benzo[d] [1,2,3]triazole 2-(4-(6-Chloropyridin-2-yl)but-3-yny)-2H-benzo [d] [1,2,3]triazole 2-(4-(6-(1-Fluoroethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole 2-(4-(4,5-Dimethylthiazol-2-yl)but-3-yny)-2H-benzo[d][1,2,3]triazole 2-(4-(Pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 2-(4-(6-(Fluoromethy)pyridin-2-yl)but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H) one 2-(4-(4-Methylthiazol-2-yl)but-3-ynyl)-2H-benzo[d] [1,2,3]triazole 8-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-y)but-3-ynyl)-imidazo[1,2-a]pyridine 8-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine 6-fluoro-2-(4-(2-(fluoromethyl)tbiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 8-(benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine 6,8-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine 6,8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine and pharmaceutically acceptable salts thereof.
24. A compound according to claims 1 to 23, which can exist as optical isomers, wherein said compound is either the racemic mixture or one or both of the individual optical isomers.
25. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 3 to 16, 20 to 24 and a pharmaceutically acceptable carrier and/or excipient.
26. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 17 to 19, 21, 22, and 24 and a pharmaceutically acceptable carrier and/or excipient.
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1 and 2 and a pharmaceutically acceptable carrier and/or excipient.
28. A method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 allosteric modulators, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
29. A method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluRS negative allosteric modulators, comprising administering to a mammal in need of such WO 2005/123703 PCT/IB2005/002390 300 treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
30. A method useful for treating or preventing central nervous system disorders selected from the group consisting of: addiction, tolerance or dependence, affective disorders, such as depression and anxiety, psychiatric disease such as psychotic disorders, attention deficit/hyperactivity disorder and bipolar disorder; Parkinson's disease, memory impairment, Alzheimer's disease, dementia, delirium tremens, other forms of neurodegeneration, neurotoxicity, and ischemia, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition according to claims 1 to 27.
31. A method useful for treating or preventing inflammatory or neuropathic pain comprising administering to a mammalian patient in need of such treatment an effective amount of a compound/composition according to claims 1 to 27.
32. A method useful for treating behaviour disorders and dependence disorders including alcohol, nicotine, cocaine, amphetamine, benzodiazepine, analgesics, opiate or other substance tolerance or dependence, bulimia nervosa, anorexia nervosa, gambling dependence, sex dependence, or obsessive compulsive disorders, comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
33. A method useful for treating alcohol, nicotine, cocaine, amphetamine, benzodiazepine, opiate or other substance abuse or addiction or withdrawal comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
34. A method useful for treating affective disorders, anxiety, panic disorder, phobia, posttraumatic stress disorder, generalized anxiety disorder, seasonal affective disorders, acute stress disorder comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
35. A method useful for treating migraine comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
36. A method useful for treating obesity comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27. WO 2005/123703 PCT/IB2005/002390 301
37. A method useful for treating gastrointestinal disorders, particularly of gastro-esophageal reflux disease (GERD) comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
38. A method useful for treating inherited disorders such as Fragile X syndrome and autism comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
39. A method useful for treating schizophrenia, depression and attention deficit/hyperactivity disorder comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims I to 27.
40. A method according to claim 30 wherein said neurological disorders is selected from the group of neurodegencration, neurotoxicity or ischemia such as Parkinson's disease, memory impairment, Alzheimer's disease, dementia, delirium tremens comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound/composition according to claims 1 to 27.
41. Use of a compound/composition according to claims I to 27 in the manufacture of a medicament for a treatment or prevention as defined in any of claims 30 to 40.
42. The use of a compound according to any of claims 1 to 24 to prepare a tracer for imaging metabotropic glutamate receptors.
43. A process for producing a compound according to claim 20 having the formula II-A2-b G 1 G 2 G 3 W tN- G4 G 5 II-A2-b Wherein W is heteroaryl selected from the group of formula: N S RR2 R R2 N R WO 2005/123703 PCT/IB2005/002390 302 R', R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C-C 6 -alkyl, Cl-C 6 -alkylhalo, aryl, Co-C 6 -alkyl-OR 5 , Co-C 6 -alkyl-NRR, Co-C 6 alkyl-NRC(=O)-R or Co-C 6 -alkyl-NsS(=0) 2 -R 6 substituents; R 5 and R 6 are each independently selected from the group consisting of hydrogen, an optionally substituted C-C 6 -alkyl, Ci-C 6 -alkylhalo, C 3 C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C-Co-alkyl, heteroaryl, C-C 6 -alkyl heteroaryl, aryl; X is selected from an optionally substituted GI-C 6 -alkyl or C 1 -C 6 alkylhalo; G', G2, G3, G4 and G 5 groups are each independently selected from the group consisting of hydrogen, halogen, nitro, an optionally substituted CI-C 6 alkyl, CI-C 6 -alkylhalo, Co-C 6 -alkyl-OR, O-Co-C 6 -alkylaryl, heteroaryl, aryl, Co-C 6 -alkyl-NR or Co-C 6 -alkyl-NR 7 -S(=0) 2 R substituents; R 7 and R 8 are each independently selected from hydrogen, an optionally substituted CI-C 6 -alkyl, Cl-C 6 -alkylhalo; Any N may be an N-oxide; Which comprises allowing a compound of formula C Si L 2 / x 0 C wherein L 2 is selected from halides such as Cl, Br, I or trifluoromethanesulfonyl and paratoluenesulfonyl; to react with the amino pyridine of formula D G2 N -G 3 H 2 N 4 G 5 D and then after deprotection giving the ethynyl-alkyl compound E G 1 G 2 NG3 X-? N- G4 G 5 E Which is then coupled with the heterocycloalkyl halide F WO 2005/123703 PCT/IB2005/002390 303 L 3 F Wherein L 3 is selected from halogen, trifluoromethane sulfonyl and paratoluene sulfonyl; is performed in the presence of a palladium catalyst and a base such as triethylamine.
AU2005254808A 2004-06-17 2005-06-17 Alkynyl derivatives as modulators of metabotropic glutamate receptors Active AU2005254808B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2012205182A AU2012205182A1 (en) 2004-06-17 2012-07-17 Alkynyl derivatives as modulators of metabotropic glutamate receptors

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB0413605.7 2004-06-17
GBGB0413605.7A GB0413605D0 (en) 2004-06-17 2004-06-17 Novel compounds
PCT/IB2005/002390 WO2005123703A2 (en) 2004-06-17 2005-06-17 Alkynyl derivatives as modulators of metabotropic glutamate receptors

Related Child Applications (1)

Application Number Title Priority Date Filing Date
AU2012205182A Division AU2012205182A1 (en) 2004-06-17 2012-07-17 Alkynyl derivatives as modulators of metabotropic glutamate receptors

Publications (2)

Publication Number Publication Date
AU2005254808A1 true AU2005254808A1 (en) 2005-12-29
AU2005254808B2 AU2005254808B2 (en) 2012-04-19

Family

ID=32750115

Family Applications (1)

Application Number Title Priority Date Filing Date
AU2005254808A Active AU2005254808B2 (en) 2004-06-17 2005-06-17 Alkynyl derivatives as modulators of metabotropic glutamate receptors

Country Status (24)

Country Link
US (3) US8101637B2 (en)
EP (2) EP2426115A3 (en)
JP (2) JP5053840B2 (en)
KR (1) KR101200175B1 (en)
CN (2) CN101001846B (en)
AU (1) AU2005254808B2 (en)
BR (1) BRPI0511072B8 (en)
CA (1) CA2570987C (en)
CY (1) CY1114582T1 (en)
DK (1) DK1765795T3 (en)
EA (2) EA012206B1 (en)
ES (1) ES2404034T3 (en)
GB (1) GB0413605D0 (en)
HK (1) HK1101178A1 (en)
IL (1) IL179692A (en)
MX (1) MXPA06014721A (en)
NO (1) NO339660B1 (en)
NZ (1) NZ551664A (en)
PL (1) PL1765795T3 (en)
PT (1) PT1765795E (en)
SI (1) SI1765795T1 (en)
UA (1) UA87856C2 (en)
WO (1) WO2005123703A2 (en)
ZA (1) ZA200610023B (en)

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0413605D0 (en) * 2004-06-17 2004-07-21 Addex Pharmaceuticals Sa Novel compounds
GB0420722D0 (en) * 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
GB2431173B (en) * 2005-09-15 2010-01-13 Alexium Ltd Method for attachment of silicon-containing compounds to a surface
US8815351B2 (en) * 2005-09-15 2014-08-26 The United States Of America As Represented By The Secretary Of The Air Force Method for attachment of silicon-containing compounds to a surface and for synthesis of hypervalent silicon-compounds
TWI417095B (en) 2006-03-15 2013-12-01 Janssen Pharmaceuticals Inc 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mglur2-receptors
JP2009531390A (en) * 2006-03-31 2009-09-03 ノバルティス アクチエンゲゼルシャフト Organic compounds
AR064563A1 (en) * 2007-01-03 2009-04-08 Bayer Cropscience Ag DERIVATIVES OF N-ALQUINILBENZAMIDA, A PROCEDURE FOR ITS PREPARATION, A FUNGITIVE COMPOSITION THAT UNDERSTANDS IT AND ITS USE IN A METHOD TO COMBAT FITOPATOGEN FUNGI.
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
JP5133416B2 (en) 2007-09-14 2013-01-30 オルソー−マクニール−ジャンセン ファーマシューティカルズ， インコーポレイテッド． 1 ', 3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H, 1'H- [1,4'] bipyridinyl-2'-one
AU2008297876B2 (en) 2007-09-14 2011-07-07 Addex Pharma S.A. 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones
US8722894B2 (en) 2007-09-14 2014-05-13 Janssen Pharmaceuticals, Inc. 1,3-disubstituted-4-phenyl-1H-pyridin-2-ones
CN101861316B (en) 2007-11-14 2013-08-21 奥梅-杨森制药有限公司 Imidazo[1,2-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
CN101965336B (en) 2008-01-04 2015-06-17 英特利凯恩有限责任公司 Certain chemical entities, compositions and methods
EP2344470B1 (en) 2008-09-02 2013-11-06 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
CN102186477B (en) 2008-10-16 2013-07-17 奥梅-杨森制药有限公司 Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors
CN102232074B (en) 2008-11-28 2014-12-03 奥梅-杨森制药有限公司 Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
BRPI1010831A2 (en) 2009-05-12 2016-04-05 Addex Pharmaceuticals Sa 1,2,4-triazolo [4,3-a] pyridine derivatives and their as positive allosteric modulators of mglur2 receptors
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
RS53075B (en) 2009-05-12 2014-04-30 Janssen Pharmaceuticals Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders
CA2778949C (en) 2009-10-30 2018-02-27 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as pde10 inhibitors
US8586581B2 (en) 2009-12-17 2013-11-19 Hoffmann-La Roche Inc Ethynyl compounds useful for treatment of CNS disorders
AR080754A1 (en) 2010-03-09 2012-05-09 Janssen Pharmaceutica Nv IMIDAZO DERIVATIVES (1,2-A) PIRAZINA AND ITS USE AS PDE10 INHIBITORS
WO2011161645A1 (en) 2010-06-25 2011-12-29 Ranbaxy Laboratories Limited 5-lipoxygenase inhibitors
US8642626B2 (en) 2010-07-29 2014-02-04 Taisho Pharmaceutical Co., Ltd. Ethinyl-pyrazole derivative
AU2011328195B2 (en) 2010-11-08 2015-04-02 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
PT2649069E (en) 2010-11-08 2015-11-20 Janssen Pharmaceuticals Inc 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
CA2815002C (en) 2010-11-08 2019-10-22 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
DK2663309T3 (en) 2011-01-10 2017-06-19 Infinity Pharmaceuticals Inc METHODS FOR PRODUCING ISOQUINOLINONES AND SOLID FORMS OF ISOQUINOLINONES
US20140228398A1 (en) 2011-03-18 2014-08-14 Novartis Ag COMBINATIONS OF ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR ACTIVATORS AND mGluR5 ANTAGONISTS FOR USE IN DOPAMINE INDUCED DYSKINESIA IN PARKINSON'S DISEASE
EP2705024B1 (en) * 2011-05-03 2015-12-16 Merck Sharp & Dohme Corp. Alkyne benzotriazole derivatives
BR112013033375B1 (en) 2011-06-27 2022-05-10 Janssen Pharmaceutica N.V Derivatives of 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline, their use, pharmaceutical composition that comprises them, process of preparation thereof, sterile solution and intermediate compound
KR101844880B1 (en) * 2011-09-26 2018-04-03 닛토덴코 가부시키가이샤 Highly-fluorescent and photo-stable chromophores for enhanced solar harvesting efficiency
WO2013052381A2 (en) 2011-10-05 2013-04-11 Nitto Denko Corporation Wavelength conversion film having pressure sensitive adhesive layer to enhance solar harvesting efficiency
GB201204962D0 (en) 2012-03-21 2012-05-02 Addex Pharmaceuticals Sa Pharmaceutical combination products for parkinsons disease
GB201210530D0 (en) * 2012-06-13 2012-07-25 Addex Pharmaceuticals Sa Extended release formulations
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
WO2014001314A1 (en) 2012-06-26 2014-01-03 Janssen Pharmaceutica Nv Combinations comprising pde 2 inhibitors such as 1-aryl-4-methyl- [1,2,4] triazolo [4,3-a] quinoxaline compounds and pde 10 inhibitors for use in the treatment of neurological or metabolic disorders
JP6174695B2 (en) 2012-07-09 2017-08-02 ヤンセン ファーマシューティカ エヌ．ベー． Inhibitor of phosphodiesterase 10 enzyme
GB201215033D0 (en) 2012-08-23 2012-10-10 Novartis Ag Diazepinone derivatives
JO3368B1 (en) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3367B1 (en) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
GB201317022D0 (en) * 2013-09-25 2013-11-06 Addex Pharmaceuticals Sa Polymorphs
WO2015077246A1 (en) * 2013-11-19 2015-05-28 Vanderbilt University Substituted imidazopyridine and triazolopyridine compounds as negative allosteric modulators of mglur5
IL279202B2 (en) 2014-01-21 2023-09-01 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
KR20220051273A (en) 2014-01-21 2022-04-26 얀센 파마슈티카 엔.브이. Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
MX2016010213A (en) 2014-02-07 2017-04-13 Auspex Pharmaceuticals Inc Novel pharmaceutical formulations.
US9533982B2 (en) 2014-03-20 2017-01-03 Vanderbilt University Substituted bicyclic heteroaryl carboxamide analogs as mGluR5 negative allosteric modulators
WO2015160975A2 (en) 2014-04-16 2015-10-22 Infinity Pharmaceuticals, Inc. Combination therapies
US9550778B2 (en) 2014-10-03 2017-01-24 Vanderbilt University Substituted 6-aryl-imidazopyridine and 6-aryl-triazolopyridine carboxamide analogs as negative allosteric modulators of mGluR5
EP3240792B1 (en) * 2014-12-29 2019-01-23 Recordati Ireland Limited Heterocyclylalkyne derivatives and their use as modulators of mglur5 receptors
JP7054681B2 (en) 2016-06-24 2022-04-14 インフィニティー ファーマシューティカルズ， インコーポレイテッド Combination therapy
EP3484528B1 (en) 2016-07-18 2020-11-25 Janssen Pharmaceutica NV Tau pet imaging ligands
BR112020005489A2 (en) 2017-09-22 2020-09-24 Jubilant Epipad Llc, compound of formula (i), compound of formula (ii), compound of formula (iii), process of preparing compounds of formula (i), process of preparing compounds of formula (ii), process of preparing compounds of formula (iii), pharmaceutical composition, method for inhibiting one or more pad families in a cell, method for treating a condition mediated by one or more pads, use of the compound, method for treating and / or preventing a condition mediated by one or more more disorders of the pad family, method for treating rheumatoid arthritis and cancer treatment method
MX2020003341A (en) 2017-10-18 2020-09-17 Jubilant Epipad LLC Imidazo-pyridine compounds as pad inhibitors.
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
CN111542523B (en) 2017-11-24 2024-03-29 朱比连特埃皮斯科瑞有限责任公司 Heterocyclic compounds as PRMT5 inhibitors
AU2019234185A1 (en) 2018-03-13 2020-10-01 Jubilant Prodel LLC. Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
CN110256480B (en) * 2019-07-23 2022-01-11 广东工业大学 Alkynyl-containing nitrogen-containing heterocyclic derivative and preparation method and application thereof

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1218326B (en) 1982-07-23 1990-04-12 Montedison Spa 1-PHENOXY (FENILTIO) -4-ARILALKINYL OXY-BENZENE DERIVED BY HORMONIC ACTION YOUTH AND ACARICIDE
DE4029654A1 (en) * 1990-09-19 1992-04-02 Hoechst Ag 2-PHENYL-PYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF, AGENTS CONTAINING IT AND THEIR USE AS FUNGICIDES
US5273977A (en) * 1990-11-05 1993-12-28 Warner-Lambert Company Substituted tetrahydropyridines and hydroxypiperidines as central nervous system agents
FR2670685B1 (en) * 1990-12-20 1995-03-10 Rhone Poulenc Chimie PROCESS FOR THE PREPARATION OF COATED CATALYSTS BASED ON BISMUTH AND IRON MOLYBDATES DOPED WITH PHOSPHORUS AND POTASSIUM.
AU721325B2 (en) * 1995-05-30 2000-06-29 Gliatech Inc. 1H-4(5)-substituted imidazole derivatives
TW544448B (en) * 1997-07-11 2003-08-01 Novartis Ag Pyridine derivatives
JP4815083B2 (en) * 1999-08-31 2011-11-16 メルク・シャープ・エンド・ドーム・コーポレイション Heterocyclic compounds and methods of use thereof
GT200100103A (en) 2000-06-09 2002-02-21 NEW HERBICIDES
KR20080064908A (en) * 2000-06-28 2008-07-09 테바 파마슈티컬 인더스트리즈 리미티드 Carvedilol
SK8402003A3 (en) 2000-12-04 2004-04-06 Hoffmann La Roche Phenylethenyl or phenylethinyl derivatives as glutamate receptor or antagonists
AR035087A1 (en) * 2001-08-09 2004-04-14 Syngenta Participations Ag PIRIDIL-ALQUINOS AND PIRIDIL-N-OXIDO-ACTIVE HERBICIDE ALKINES, PROCEDURE FOR PREPARATION, HERBICIDE COMPOSITION AND TO INHIBIT THE GROWTH OF PLANTS, METHOD FOR CONTROLLING GROWTH OF INDESEABLE PLANTS, AND METHOD OF CREAM INHIBITION
BR0212794A (en) 2001-09-13 2004-10-05 Synta Pharmaceuticals Corp 1-Glyoxylamide Indolizine Compound and its Use
AR037754A1 (en) * 2001-12-11 2004-12-01 Syngenta Participations Ag HERBICIDES
WO2003093236A1 (en) 2002-05-02 2003-11-13 Euro-Celtique, S.A. 1-(pyrid-2-yl)-piperazine compounds as metabotropic glutamate receptor inhibitor
AR040413A1 (en) * 2002-05-31 2005-04-06 Syngenta Participations Ag HETEROCICLILALQUINOS ACTIVE AS HERBICIDES
WO2004038374A2 (en) 2002-10-24 2004-05-06 Merck & Co., Inc. Alkyne derivatives as tracers for metabotropic glutamate receptor binding
DE10250708A1 (en) 2002-10-31 2004-05-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg New alkyne compounds having MCH antagonist activity and medicaments containing these compounds
US7452911B2 (en) 2002-10-31 2008-11-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
JP2006519251A (en) 2003-03-04 2006-08-24 アデックス ファーマシューティカルズ ソシエテ アノニム Novel aminopyridine derivatives as mGluR5 antagonists
JP4673293B2 (en) * 2003-03-07 2011-04-20 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト Process for the production of substituted nicotinic acid esters
EP1682135B1 (en) * 2003-10-27 2011-07-27 Merck Sharp & Dohme Corp. salt of a tetrahydropyranyl cyclopentyl tetrahydropyridopyridine derivative as CCR2-antagonist
WO2005044267A1 (en) * 2003-10-31 2005-05-19 Astrazeneca Ab Alkynes ii
JP2007510645A (en) * 2003-10-31 2007-04-26 アストラゼネカ アクチボラグ Alkynes I
WO2005044265A1 (en) * 2003-10-31 2005-05-19 Astrazeneca Ab Alkynes iii
KR20060131958A (en) * 2004-04-02 2006-12-20 에프. 호프만-라 로슈 아게 New process for the preparation of diazine derivatives
GB0413605D0 (en) 2004-06-17 2004-07-21 Addex Pharmaceuticals Sa Novel compounds

Also Published As

Publication number Publication date
GB0413605D0 (en) 2004-07-21
KR20070054624A (en) 2007-05-29
IL179692A0 (en) 2007-05-15
EA012206B1 (en) 2009-08-28
JP5053840B2 (en) 2012-10-24
CN102993084A (en) 2013-03-27
KR101200175B1 (en) 2012-11-13
CA2570987C (en) 2013-12-03
NO339660B1 (en) 2017-01-16
CN101001846A (en) 2007-07-18
JP2008502674A (en) 2008-01-31
CY1114582T1 (en) 2016-10-05
EP1765795B1 (en) 2013-03-06
US20120277237A1 (en) 2012-11-01
NO20070288L (en) 2007-01-16
HK1101178A1 (en) 2007-10-12
US8674106B2 (en) 2014-03-18
EA200700047A1 (en) 2007-06-29
EP2426115A3 (en) 2014-09-03
WO2005123703A3 (en) 2006-10-12
JP2012051937A (en) 2012-03-15
US20130178631A1 (en) 2013-07-11
EP1765795A2 (en) 2007-03-28
ZA200610023B (en) 2008-08-27
US20090124625A1 (en) 2009-05-14
BRPI0511072B1 (en) 2019-08-27
PT1765795E (en) 2013-04-17
PL1765795T3 (en) 2013-07-31
US8101637B2 (en) 2012-01-24
IL179692A (en) 2011-02-28
NZ551664A (en) 2010-08-27
ES2404034T3 (en) 2013-05-23
AU2005254808B2 (en) 2012-04-19
EA200970326A1 (en) 2009-12-30
WO2005123703A8 (en) 2007-02-15
DK1765795T3 (en) 2013-06-03
BRPI0511072A (en) 2007-11-27
UA87856C2 (en) 2009-08-25
SI1765795T1 (en) 2013-06-28
CN101001846B (en) 2012-11-07
EP2426115A2 (en) 2012-03-07
CA2570987A1 (en) 2005-12-29
BRPI0511072B8 (en) 2021-05-25
WO2005123703A2 (en) 2005-12-29
MXPA06014721A (en) 2007-06-22
CN102993084B (en) 2015-05-20
US8883826B2 (en) 2014-11-11

Similar Documents

Publication Publication Date Title
AU2005254808B2 (en) Alkynyl derivatives as modulators of metabotropic glutamate receptors
JP5820538B2 (en) 1,2,4-triazole as an allosteric modulator of mGlu5 receptor activity for the treatment of schizophrenia in dementia
US9573936B2 (en) Triazole agonists of the APJ receptor
AU2002341921B8 (en) Heteroaryl substituted tetrazole modulators of metabotropic glutamate receptor-5
JP4559087B2 (en) Triazole derivatives as tachykinin receptor antagonists
AU2009292931B2 (en) Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases
EA028626B1 (en) Tnf-alpha modulating benzimidazoles
US20150203479A1 (en) Androgen receptor modulating compounds
AU2007267183A1 (en) Aryl-4-ethynyl-isoxazole derivatives
JP2021519263A (en) Compounds and their use
RU2412181C2 (en) Heteroaryl-substituted amides containing saturated binding group and use thereof as pharmaceutical agents
AU2012205182A1 (en) Alkynyl derivatives as modulators of metabotropic glutamate receptors
AU2016378154B2 (en) Phenylimidazole compound
AU2013213705A1 (en) Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases

Legal Events

Date Code Title Description
TC Change of applicant's name (sec. 104)

Owner name: ADDEX PHARMA SA

Free format text: FORMER NAME: ADDEX PHARMACEUTICALS SA

FGA Letters patent sealed or granted (standard patent)